Thiazoline derivative and use of the same

ABSTRACT

A thiazoline derivative represented by Formula (I):  
                 
 
wherein R is a cyclic hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted; X is a bond or a divalent chain hydrocarbon group which may be substituted; X′ is a bond or —N(R 5 )—; Y is a divalent hydrocarbon group which may be substituted; Y′ is a bond or —C(═O)—; ring A is a nitrogen-containing heterocycle which may be substituted; Z 1  and Z 3  are each independently a bond or a divalent chain hydrocarbon group which may be substituted; Z 2  is a bond or —N(R 6 )—; and B is a group represented by the formula:  
                 
which is useful as a therapeutic drug for thrombosis, is provided.

TECHNICAL FIELD

The present invention relates to a novel thiazoline derivative having ananti-coagulating effect and an anti-thrombotic effect by inhibitingactivated blood coagulation factor X (FXa), which is useful forpreventing and treating arterial and venous thrombotic obstructivediseases, inflammation, cancer and the like, and use of the same.

BACKGROUND ART

It is important to suppress the formation of thrombi for preventing andtreating myocardial infarction, cerebral thrombosis and the like, andvarious antithrombin agents, platelet aggregation inhibitors and thelike have been studied and developed as thrombosis inhibitors. However,since not only platelet aggregation inhibitors, but also anti-thrombinagents suppress the aggregation of platelets in addition to theiranticoagulant activity, these medicaments tend to cause bleeding and thelike as adverse side-effects. Therefore, there is a problem in theirsafety. On the other hand, it is considered that the FXa inhibitor is asafe anticoagulant agent for specifically inhibiting only coagulatingfactor. Hitherto, compounds having the FXa inhibiting activity have beendisclosed, for example, in the following publications. JP 7-112970 A, JP5-208946 A, WO 96/16940, WO 96/40679, WO 96/10022, WO 97/21437, WO99/26919, WO 99/33805, WO 00/09480, WO 01/44172, WO 02/06234, US2002/0045616 A, WO 2004/035579, WO 2004/048363, and Journal of MedicinalChemistry, 1998, Vol. 41, page 3357.

OBJECT OF THE INVENTION

Development of a novel compound is desired, which has excellentefficacy, oral absorbability, sustained effect and the like, with fewerside effects, and which is more useful as a therapeutic agent forthrombosis, as compared with conventional FXa inhibitors.

DISCLOSURE OF THE INVENTION

The inventors of the present invention envisaged that a thiazolinederivative having high selectivity for and strong inhibiting actionagainst FXa can exhibit a persistent and sufficient effect upon oraladministration, and thus would be useful for prevention and treatment ofthrombotic occlusive diseases in arteries and veins, inflammation,cancer and the like. Thus, they have devotedly continued their study.

As a result, the inventors have found that a novel thiazoline derivativerepresented by the following Formula (I), or a salt thereof(hereinafter, may be referred to as Compound (I)) has a selectivelystrong FXa inhibiting effect and excellent safety, and thus exhibits asustained and sufficient effect upon oral administration, thuscompleting the invention.

Thus, the invention relates to:

(1) A compound represented by Formula (I):

wherein R is a cyclic hydrocarbon group which may be substituted or aheterocyclic group which may be substituted; X is a bond or a divalentchain hydrocarbon group which may be substituted; X′ is a bond or—N(R⁵)— (wherein R⁵ is a hydrogen atom, a hydrocarbon group which may besubstituted, an esterified or amidated carboxyl group, or an acylgroup); Y is a divalent hydrocarbon group which may be substituted; Y′is a bond or —C(═O)—; ring A is a nitrogen-containing heterocycle whichmay be substituted; Z¹ and Z³ are each independently a bond or adivalent chain hydrocarbon group which may be substituted; Z² is a bondor —N(R⁶)— (wherein R⁶ is a hydrogen atom, a hydrocarbon group which maybe substituted, or an acyl group); B is a group represented by theformula:

(wherein R¹ and R² are each independently a hydrogen atom, a halogenatom, a hydrocarbon group which may be substituted, an alkoxy groupwhich may be substituted, a carboxyl group which may be esterified oramidated, an acyl group, or an amino group which may be substituted; R³is a hydrogen atom, a hydrocarbon group which may be substituted, acarboxyl group which may be esterified or amidated, or an acyl group; R⁴is a hydrocarbon group which may be substituted; and R² and R¹ or R⁴,and R³ and R⁴ may be respectively bonded to each other to form a ringwhich may be substituted); R⁶ and R¹, R², R³ or R⁴ may be bonded to eachother to form a ring which may be substituted; and a is 0, 1 or 2, or asalt thereof;

(2) A prodrug of the compound according to the above-mentioned (1);

(3) The compound according to the above-mentioned (1), wherein R is anaryl group which may be substituted with a substituent selected from ahalogen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, amino which may besubstituted, nitro, cyano, amidino which may be substituted, andcarboxyl which may be esterified or amidated;

(4) The compound according to the above-mentioned (1), wherein R is aheterocyclic group which may be substituted with a substituent selectedfrom a halogen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, amino whichmay be substituted, nitro, cyano, amidino which may be substituted, andcarboxyl which may be esterified or amidated;

(5) The compound according to the above-mentioned (1), wherein R isnaphthyl which may be substituted with a halogen atom;

(6) The compound according to the above-mentioned (1), wherein X is abond, X′ is a bond, Y is C₁₋₃ alkylene which may be substituted, and Y′is —C(═O)—;

(7) The compound according to the above-mentioned (6), wherein Y is C₁₋₃alkylene substituted with a hydroxyl group;

(8) The compound according to the above-mentioned (1), wherein Z¹ and Z²are each a bond, and Z³ is C₁₋₃ alkylene which may be substituted;

(9) The compound according to the above-mentioned (1), wherein ring A isa piperazine ring which may be substituted or a piperidine ring whichmay be substituted;

(10) The compound according to the above-mentioned (1), wherein ring Ais a ring represented by the formula:

wherein ring A′ may be further substituted, or the formula:

wherein ring A″ may be further substituted;

(11) The compound according to the above-mentioned (1), wherein R⁵ is ahydrogen atom;

(12) The compound according to the above-mentioned (1), wherein a is 2;

(13) A compound selected from the group consisting ofN-(4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine,4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-imine,N-(5-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine,5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-imine,and2-(2-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)imino)-1,3-thiazol-3(2H)-yl)ethanol,or a salt thereof or a prodrug thereof;

(14) A compound represented by Formula (II′):

wherein P⁰ is a hydrogen atom, or a protective group of an imino group;and the other symbols have the same meanings as defined in theabove-mentioned (1), or a salt thereof;

(15) A pharmaceutical composition comprising the compound according tothe above-mentioned (1) or (2);

(16) The pharmaceutical composition according to the above-mentioned(15), which is an anticoagulant;

(17) The pharmaceutical composition according to the above-mentioned(15), which is an activated blood coagulation factor X inhibitor;

(18) The pharmaceutical composition according to the above-mentioned(15), which is a medicament for preventing or treating myocardialinfarction, cerebral infarction, deep vein thrombosis, pulmonarythromboembolism or atherosclerotic obliterans;

(19) The pharmaceutical composition according to the above-mentioned(15), which is a medicament for preventing or treating economy-classsyndrome, thromboembolism during and post operation, or the secondaryonset of deep vein thrombosis;

(20) A method for inhibiting blood coagulation in a mammal, whichcomprises administering an effective amount of the compound according tothe above-mentioned (1) or a prodrug thereof to a mammal;

(21) A method for inhibiting an activated blood coagulation factor X ina mammal, which comprises administering an effective amount of thecompound according to the above-mentioned (1) or a prodrug thereof to amammal;

(22) A method for preventing or treating myocardial infarction, cerebralinfarction, deep vein thrombosis, pulmonary thromboembolism oratherosclerotic obliterans in a mammal, which comprises administering aneffective amount of the compound according to the above-mentioned (1) ora prodrug thereof to a mammal;

(23) Use of the compound according to the above-mentioned (1) or aprodrug thereof, for manufacturing a medicament for inhibiting bloodcoagulation;

(24) Use of the compound according to the above-mentioned (1) or aprodrug thereof, for manufacturing a medicament for inhibiting anactivated blood coagulation factor X;

(25) Use of the compound according to the above-mentioned (1) or aprodrug thereof, for manufacturing a medicament for preventing ortreating myocardial infarction, cerebral infarction, deep veinthrombosis, pulmonary thromboembolism or atherosclerotic obliterans; andthe like.

In the above-described formulas, R is a cyclic hydrocarbon group whichmay be substituted, or a heterocyclic group which may be substituted(preferably, an aryl group which may be substituted, or an aromaticheterocyclic group which may be substituted).

The “cyclic hydrocarbon group” of the “cyclic hydrocarbon group whichmay be substituted” represented by R, may be exemplified by an alicyclichydrocarbon group, an aryl group or the like. Among them, an aryl groupor the like is preferred.

The “alicyclic hydrocarbon group” as an example of the cyclichydrocarbon group may be exemplified by a saturated or unsaturatedalicyclic hydrocarbon group such as a cycloalkyl group, a cycloalkenylgroup, a cycloalkadienyl group or the like.

Here, the “cycloalkyl group” may be exemplified by a C₃-₉ cycloalkylgroup such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl or cyclononyl, or the like (preferably, a C₅₋₇cycloalkyl group or the like).

The “cycloalkenyl group” may be exemplified by a C₃₋₉ cycloalkenyl groupsuch as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl,3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl,1-cyclohexen-1-yl or 1-cyclohepten-1-yl, or the like (preferably, a C₅₋₇cycloalkenyl group or the like).

The “cycloalkadienyl group” may be exemplified by a C₄₋₆ cycloalkadienylgroup such as 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl or2,5-cyclohexadien-1-yl, or the like.

The “aryl group” as an example of the cyclic hydrocarbon group may beexemplified by a monocyclic or fused polycyclic aromatic hydrocarbongroup, and for example, a C₆₋₁₄ aryl group such as phenyl, naphthyl,anthryl, phenanthryl or acenaphthylenyl, and the like are preferred,with phenyl, 1-naphthyl, 2-naphthyl and the like among them beingparticularly preferred.

Examples of the cyclic hydrocarbon group further include a bicyclic ortricyclic hydrocarbon group derived from condensation of identical ordifferent 2 to 3 rings (preferably, rings of two or more species) thatare selected from the rings constituting the above-described alicyclichydrocarbon groups and aromatic hydrocarbon groups, such as1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, indenyl,dihydrobenzocycloheptenyl and fluorenyl, and the like.

The “heterocyclic group” of the “heterocyclic group which may besubstituted” represented by R, may be exemplified by an aromaticheterocyclic group, a saturated or unsaturated non-aromatic heterocyclicgroup (aliphatic heterocyclic group) or the like, respectivelycontaining at least one (preferably 1 to 3, more preferably 1 to 2)heteroatom of 1 to 3 species (preferably 1 to 2 species) selected fromoxygen, sulfur and nitrogen atoms and the like, as the atom constitutingthe ring system (ring atom).

Examples of the “aromatic heterocyclic group” may be exemplified by a 5-to 6-membered aromatic monocyclic heterocyclic group such as furyl,thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl or the like; anda 8- to 16-membered (preferably, 10- to 12-membered) aromatic fusedheterocyclic group (preferably, a heterocyclic group derived from aheterocycle resulting from condensation of 1 to 2 (preferably, one)heterocycles constituting the above-described 5- to 6-membered aromaticmonocyclic heterocyclic group, with 1 to 2 benzene rings (preferably,one), or a heterocyclic group derived from a heterocycle resulting fromcondensation of 2 to 3 (preferably, two) identical or differentheterocycles constituting the above-described 5- to 6-membered aromaticmonocyclic heterocyclic group, more preferably a heterocyclic groupderived from a heterocycle resulting from condensation of a heterocycleconstituting the above-described 5- to 6-membered aromatic monocyclicheterocyclic group, with a benzene ring, and particularly preferablyindolyl, benzofuranyl, benzo[b]thienyl, benzopyranyl or the like), suchas benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl,1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl,benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl,quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl,phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl,α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl,phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[l,2-a]pyridyl, imidazo[l,5-a]pyridyl, imidazo[1,2-b]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, or1,2,4-triazolo[4,3-b]pyridazinyl; or the like.

Examples of the “non-aromatic heterocyclic group” include a 3- to8-membered (preferably, 5- to 6-membered) saturated or unsaturated(preferably, saturated) non-aromatic monocyclic heterocyclic group(aliphatic monocyclic heterocyclic group) such as oxiranyl, azetidinyl,oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl,piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinylor the like; a heterocyclic group derived from a heterocycle resultingfrom condensation of 1 to 2 (preferably, one) heterocycles whichconstitute the above-described non-aromatic monocyclic heterocyclicgroup such as 1,3-dihydroisoindolyl or the like, with 1 to 2(preferably, one) benzene rings; a heterocyclic group derived from aheterocycle resulting from condensation of 1 to 2 (preferably, one)heterocycles which constitute the above-described non-aromaticmonocyclic heterocyclic group, with 1 to 2 (preferably, one)heterocycles which constitute the above-described 5- to 6-memberedaromatic monocyclic heterocyclic group; or a non-aromatic heterocyclicgroup resulting from saturation of part or all of the double bonds inthe above-described aromatic monocyclic heterocyclic group or aromaticfused heterocyclic group, such as 1,2,3,4-tetrahydroquinolyl,1,2,3,4-tetrahydroisoquinolyl or the like; and the like.

Examples of the substituent for the “cyclic hydrocarbon group which maybe substituted” and the “heterocyclic group which may be substituted”represented by R, include alkyl which may be substituted, alkenyl whichmay be substituted, alkynyl which may be substituted, aryl which may besubstituted, cycloalkyl which may be substituted, cycloalkenyl which maybe substituted, heterocyclic group which may be substituted, amino whichmay be substituted, imidoyl which may be substituted [for example, agroup represented by the formula: —C(U′)═N—U, wherein U and U′ are eacha hydrogen atom or a substituent for imidoyl (U is preferably a hydrogenatom), etc.], amidino which may be substituted [for example, a grouprepresented by the formula —C(NT′T″)═N—T, wherein T, T′ and T″ are eacha hydrogen atom or a substituent for amidino (T is preferably a hydrogenatom), etc.], hydroxyl which may be substituted, thiol which may besubstituted, carboxyl which may be esterified or amidated, thiocarbamoylwhich may be substituted, sulfamoyl which may be substituted, halogenatom (e.g., fluorine, chlorine, bromine, iodine, etc., preferablychlorine, bromine, etc.), cyano, nitro, acyl (carboxylic acid-derivedacyl, sulfonic acid-derived acyl, sulfinic acid-derived acyl), and thelike. Any of these substituents may be substituted at 1 to 5(preferably, 1 to 3) substitutable positions. Also, the “cyclichydrocarbon group which may be substituted” and the “heterocyclic groupwhich may be substituted” represented by R may have an oxo group or athioxo group, and for example, when R is benzopyranyl, R may formbenzo-α-pyronyl, benzo-γ-pyronyl or the like.

The “aryl” of the “aryl which may be substituted” as a substituent forthe “cyclic hydrocarbon group which may be substituted” and the“heterocyclic group which may be substituted” represented by R, may beexemplified by C₆₋₁₄ aryl such as phenyl, naphthyl, anthryl, phenanthrylor acenaphthylenyl, or the like. Here, the substituent which may becarried by the aryl may be exemplified by lower alkoxy (e.g., C₁₋₆alkoxy such as methoxy, ethoxy or propoxy, etc.), a halogen atom (e.g.,fluorine, chlorine, bromine, iodine, etc.), lower alkyl (e.g., C₁₋₆alkyl such as methyl, ethyl or propyl, etc.), lower alkenyl (e.g., C₂₋₆alkenyl such as vinyl or allyl, etc.), lower alkynyl (e.g., C₂₋₆ alkynylsuch as ethynyl or propargyl, etc.), amino which may be substituted,hydroxyl which may be substituted, cyano, amidino which may besubstituted, carboxyl, lower alkoxycarbonyl (e.g., C₁₋₆ alkoxycarbonylsuch as methoxycarbonyl or ethoxycarbonyl, etc.), carbamoyl which may besubstituted (e.g., carbamoyl which may be substituted with C₁₋₆ alkyl oracyl (e.g., formyl, C₂₋₆ alkanoyl, benzoyl, C₁₋₆ alkoxycarbonyl whichmay be halogenated, C₁₋₆ alkylsulfonyl which may be halogenated,benzenesulfonyl, etc.) which may be substituted with a 5- to 6-memberedaromatic monocyclic heterocyclic group (e.g., pyridinyl, etc.),1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl,morpholinocarbonyl, thiomorpholinocarbonyl (the sulfur atom may beoxidized), 1-piperazinylcarbonyl, etc.), or the like. Any of thesesubstituents may be substituted at 1 to 3 substitutable positions.

For the “amino which may be substituted”, “hydroxyl which may besubstituted” and “amidino which may be substituted” as the substituentsfor the “aryl which may be substituted” as a substituent for the “cyclichydrocarbon group which may be substituted” and the “heterocyclic groupwhich may be substituted” represented by R, mention may be made ofgroups such as the “amino which may be substituted”, “hydroxyl which maybe substituted” and “amidino which may be substituted” as thesubstituents for the “cyclic hydrocarbon group which may be substituted”and the “heterocyclic group which may be substituted” represented by Rdescribed below.

The “alkyl” of the “alkyl which may be substituted” as a substituent forthe “cyclic hydrocarbon group which may be substituted” and the“heterocyclic group which may be substituted” represented by R, may beexemplified by C₁₋₆ alkyl such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl or 3,3-dimethylpropyl or the like.Here, as the substituent for the alkyl, mention may be made of the samegroups of the same number as the substituents which may be carried bythe aryl of the above-described “aryl which may be substituted”, and anoxo group, a thioxo group, and the like.

The “alkenyl” of the “alkenyl which may be substituted” as a substituentfor the “cyclic hydrocarbon group which may be substituted” and the“heterocyclic group which may be substituted” represented by R, may beexemplified by C₂₋₆ alkenyl such as vinyl, allyl, isopropenyl,2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl,3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl or 5-hexenyl, or the like.Here, as the substituent for the alkenyl, mention may be made of thesame groups of the same number as the substituents which may be carriedby the aryl of the above-described “aryl which may be substituted”, andan oxo group, a thioxo group and the like.

The “alkynyl” of the “alkynyl which may be substituted” as a substituentfor the “cyclic hydrocarbon group which may be substituted” and the“heterocyclic group which may be substituted” represented by R, may beexemplified by C₂₋₆ alkynyl such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl, orthe like. Here, as the substituent for the alkynyl, mention may be madeof the same groups of the same number as the substituents which may becarried by the aryl of the above-described “aryl which may besubstituted”, and an oxo group, a thioxo group, and the like.

The “cycloalkyl” of the “cycloalkyl which may be substituted” as asubstituent for the “cyclic hydrocarbon group which may be substituted”and the “heterocyclic group which may be substituted” represented by R,may be exemplified by C₃₋₇ cycloalkyl such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl, or the like. Here, as thesubstituent for the cycloalkyl, mention may be made of the same groupsof the same number as the substituents which may be carried by theabove-described “aryl which may be substituted”, and an oxo group, athioxo group and the like.

The “cycloalkenyl” of the “cycloalkenyl which may be substituted” as asubstituent for the “cyclic hydrocarbon group which may be substituted”and the “heterocyclic group which may be substituted” represented by R,may be exemplified by C₃₋₆ cycloalkenyl such as cyclopropenyl,cyclobutenyl, cyclopentenyl or cyclohexenyl, or the like. Here, as thesubstituent for the cycloalkenyl which may be substituted, mention maybe made of the same groups of the same number as the substituents whichmay be carried by the aryl of the above-described “aryl which may besubstituted”, and an oxo group, a thioxo group or the like.

The “heterocyclic group” of the “heterocyclic group which may besubstituted” as a substituent” for the “cyclic hydrocarbon group whichmay be substituted” and the “heterocyclic group which may besubstituted” represented by R, may be exemplified by the same groups asthe heterocyclic groups for the “heterocyclic group which may besubstituted” represented by R, or the like.

The substituent which may be carried by the heterocyclic group for the“heterocyclic group which may be substituted”, may be exemplified by thesame groups of the same number as the substituents which may be carriedby the aryl of the above-described “aryl which may be substituted”, andan oxo group, a thioxo group and the like.

As the substituent for the “amino which may be substituted”, “imidoylwhich may be substituted”, “amidino which may be substituted”, “hydroxylwhich may be substituted” and “thiol which may be substituted” assubstituents for the “cyclic hydrocarbon group which may be substituted”and the “heterocyclic group which may be substituted” represented by R,mention may be made of, for example, lower alkyl (e.g., C₁₋₆ alkyl suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentylor hexyl, etc.) which may be substituted with a substituent selectedfrom a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc.)and C₁₋₆ alkoxy which may be halogenated (e.g., methoxy, ethoxy,trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy,2,2,2-trichloroethoxy, etc.), acyl (C₁₋₆ alkanoyl (e.g., formyl, acetyl,propionyl, pivaloyl, etc.), benzoyl, C₁₋₆ alkylsulfonyl (e.g.,methanesulfonyl, etc.), benzenesulfonyl, etc.), C₁₋₆ alkoxycarbonylwhich may be halogenated (e.g., methoxycarbonyl, ethoxycarbonyl,trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl,trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), C₁₋₆alkoxycarbonyl which may be substituted with phenyl (e.g.,benzyloxycarbonyl, etc.), a heterocyclic group (the same groups as the“heterocyclic groups” of the “heterocyclic group which may besubstituted” represented by R, etc.), and the like. The “amino” of the“amino which may be substituted” as a substituent may be substitutedwith imidoyl which may be substituted (e.g., C₁₋₆ alkylimidoyl(formylimidoyl, acetylimidoyl, etc.), C₁₋₆ alkoxyimidoyl, C₁₋₆alkylthioimidoyl, amidino, etc.), amino which may be substituted withone to two C₁₋₆ alkyl, or the like, and two substituents together with anitrogen atom may form cyclic amino. In this case, the cyclic amino maybe exemplified by 3- to 8-membered (preferably, 5- to 6-membered) cyclicamino such as 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino,morpholino, 1-piperazinyl, 1-piperazinyl which may have lower alkyl(e.g., C₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl, butyl,t-butyl, pentyl or hexyl, etc.), aralkyl (e.g., C₇₋₁₀ aralkyl such asbenzyl or phenethyl, etc.), aryl (e.g., C₆₋₁₀ aryl such as phenyl,1-naphthyl or 2-naphthyl, etc.) or the like on the 4-position,1-pyrrolyl, 1-imidazolyl, or the like.

The “carboxyl which may be esterified or amidated” as a substituent forthe “cyclic hydrocarbon group which may be substituted” and the“heterocyclic group which may be substituted” represented by R, may beexemplified by free carboxyl, esterified carboxyl, amidated carboxyl orthe like.

Examples of the “esterified carboxyl” include lower alkoxycarbonyl,aryloxycarbonyl, aralkyloxycarbonyl, and the like.

Examples of the “lower alkoxycarbonyl” include C₁₋₆ alkoxycarbonyl suchas methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl andneopentyloxycarbonyl, and the like. Among them, C₁₋₃ alkoxycarbonyl suchas methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl is preferred.

The “aryloxycarbonyl” is preferably, for example, C₆₋₁₀ aryloxycarbonylsuch as phenoxycarbonyl, 1-naphthoxycarbonyl or 2-naphthoxycarbonyl, orthe like.

The “aralkyloxycarbonyl” is preferably, for example,C₇-₁₀-aralkyloxycarbonyl such as benzyloxycarbonyl orphenethyloxycarbonyl (preferably, C₆₋₁₀ aryl-C₁₋₄ alkoxycarbonyl, etc.),or the like.

The “aryloxycarbonyl” and “aralkyloxycarbonyl” may be substituted, andas the substituent, the same groups of the same number as the groupsexemplified as the substituents for the aryl and aralkyl as theexemplary substituents for the above-described N-monosubstitutedcarbamoyl are used.

The “amidated carboxyl” may be exemplified by N-monosubstitutedcarbamoyl and N,N-disubstituted carbamoyl, in addition to unsubstitutedcarbamoyl.

The substituent for the “N-monosubstituted carbamoyl” may be exemplifiedby lower alkyl (e.g., C₁₋₆ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl, etc.), loweralkenyl (e.g., C₂₋₆ alkenyl such as vinyl, allyl, isopropenyl, propenyl,butenyl, pentenyl or hexenyl, etc.), cycloalkyl (e.g., C₃₋₆ cycloalkylsuch as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.), aryl(e.g., C₆₋₁₀ aryl such as phenyl, 1-naphthyl or 2-naphthyl, etc.),aralkyl (e.g., C₇₋₁₀ aralkyl such as benzyl or phenethyl, preferablyphenyl-C₁₋₄ alkyl, etc.), arylalkenyl (e.g., C₈₋₁₀ arylalkenyl such ascinnamyl, preferably phenyl-C₂₋₄ alkenyl, etc.), a heterocyclic group(for example, the same group as the “heterocyclic group” of theabove-described “heterocyclic group which may be substituted”represented by R, etc.), amino which may be substituted with one to twoC₁₋₆ alkyl, or the like. The lower alkyl, lower alkenyl, cycloalkyl,aryl, aralkyl, arylalkenyl and heterocyclic group may be substituted,and as the substituent, mention may be made of, for example, hydroxyl,amino which may be substituted [this amino may be substituted with 1 or2 substituents selected from, for example, lower alkyl (e.g., C₁₋₆ alkylsuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl or hexyl, etc.), acyl (e.g., C₁₋₆ alkanoyl such as formyl,acetyl, propionyl or pivaloyl, benzoyl, etc.), carboxyl, C₁₋₆alkoxycarbonyl and the like], halogen atom (for example, fluorine,chlorine, bromine, iodine, etc.), nitro, cyano, lower alkyl which may besubstituted with 1 to 5 halogen atoms (for example, fluorine, chlorine,bromine, iodine, etc.), lower alkoxy which may be substituted with 1 to5 halogen atoms (for example, fluorine, chlorine, bromine, iodine,etc.), and the like. The lower alkyl may be exemplified by C₁₋₆ alkylsuch as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl or hexyl, or the like, and particularlymethyl, ethyl and the like are preferred. The lower alkoxy may beexemplified by C₁₋₆ alkoxy such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, or the like,and particularly methoxy, ethoxy and the like are preferred. It ispreferable that 1, 2 or 3 (preferably, 1 or 2) of these substituents,whether identical or different, are used for the substitution.

The “N,N-disubstituted carbamoyl” refers to a carbamoyl group having twosubstituents on the nitrogen atom, and examples of the substituentinclude, on one side, the same groups as the substituents for theabove-described “N-monosubstituted carbamoyl, and on the other side, forexample, lower alkyl (e.g., C₁₋₆ alkyl such as methyl, ethyl, propyl,isopropyl, butyl, tert-butyl, pentyl or hexyl, etc.), C₃₋₆ cycloalkyl(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C₇₋₁₀aralkyl (e.g., benzyl, phenethyl, etc., preferably phenyl-C₁₋₄ alkyl,etc.), and the like. Further, two substituents together with thenitrogen atom may form cyclic amino, and in this case, the cyclicaminocarbamoyl may be exemplified by 3- to 8-membered (preferably, 5- to6-membered) cyclic aminocarbonyl such as 1-azetidinylcarbonyl,1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,thiomorpholinocarbonyl (the sulfur atom may be oxidized),1-piperazinylcarbonyl, and 1-piperazinylcarbonyl which may have loweralkyl (e.g., C₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, pentyl or hexyl, etc.), aralkyl (e.g., C₇₋₁₀ aralkyl such asbenzyl or phenethyl, etc.), aryl (e.g., C₆₋₁₀ aryl such as phenyl,1-naphthyl or 2-naphthyl, etc.) or the like on the 4-position, or thelike.

As the substituent for the “thiocarbamoyl which may be substituted” and“sulfamoyl which may be substituted” as the substituents for the “cyclichydrocarbon group which may be substituted” and the “heterocyclic groupwhich may be substituted” represented by R, mention may be made of thesame groups as the substituents for the above-described “carbamoyl whichmay be substituted”, or the like.

The acyl as a substituent for the “cyclic hydrocarbon group which may besubstituted” and the “heterocyclic group which may be substituted”represented by R, may be exemplified by carboxylic acid-derived acyl,sulfonic acid-derived acyl, sulfinic acid-derived acyl or the like.

The “carboxylic acid-derived acyl” may be exemplified by the groupsformed by the binding of carbonyl with a hydrogen atom, lower alkyl(e.g., C₁₋₆ alkyl such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl or hexyl, etc.), lower alkenyl (e.g., C₂₋₆alkenyl such as vinyl, allyl, isopropenyl, propenyl, butenyl, pentenylor hexenyl, etc.), cycloalkyl (e.g., C₃₋₆ cycloalkyl such ascyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, etc.), aryl (e.g.,C₆₋₁₀ aryl such as phenyl, 1-naphthly or 2-naphthyl, etc.), aralkyl(e.g., C₇₋₁₀ aralkyl such as benzyl or phenethyl, preferably phenyl-C₁₋₄alkyl, etc.), arylalkenyl (e.g., C₈₋₁₀ arylalkenyl such as cinnamyl,preferably phenyl-C₂₋₄ alkenyl, etc.), or the like. Preferably, mentionmay be made of C₁₋₆ alkanoyl such as formyl, acetyl, propionyl orpivaloyl, benzoyl, or the like.

The “sulfonic acid-derived acyl” may be exemplified by the groups formedby the binding of sulfonyl with the groups forming the above-described“carboxylic acid-derived acyl” by binding with carbonyl, or the like.Preferably, mention may be made of C₁₋₆ alkylsulfonyl such asmethanesulfonyl or ethanesulfonyl, benzenesulfonyl, toluenesulfonyl, orthe like.

The “sulfinic acid-derived acyl” may be exemplified by the groups formedby the binding of sulfinyl with the groups forming the above-described“carboxylic acid-derived acyl” by binding with carbonyl, or the like.Preferably, mention may be made of C₁₋₆ alkylsulfonyl such asmethanesulfinyl or ethanesulfinyl, or the like.

The substituent for the “cyclic hydrocarbon group which may besubstituted” and the “heterocyclic group which may be substituted”represented by R, may be a phosphono group (for example, (mono- ordi-C₁₋₄ alkyl)phosphono which may form a ring, such asdimethylphosphono, diethylphosphono, diisopropylphosphono,dibutylphosphono or 2-oxido-1,3,2-dioxaphosphinan-2-yl, etc.).

R is preferably an aryl group which may be substituted with asubstituent selected from a halogen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, amino which may be substituted, nitro, cyano, amidino which maybe substituted, and carboxyl which may be esterified or amidated; or aheterocyclic group which may be substituted with a substituent selectedfrom a halogen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, amino whichmay be substituted, nitro, cyano, amidino which may be substituted, andcarboxyl which may be esterified or amidated.

Among these, R is preferably aryl which may be substituted, and interalia, aryl (preferably, C₆₋₁₄ aryl such as phenyl, 1-naphthyl or2-naphthyl, etc.) which may be substituted with a halogen atom or C₂₋₄alkenyl (preferably, a halogen atom) is preferred.

R is also preferably a heterocyclic group which may be substituted, andinter alia, a heterocyclic group (preferably, indolyl, benzofuranyl,benzothienyl, benzopyranyl, etc., more preferably indolyl) which may besubstituted with a halogen atom is preferred.

In particular, R is preferably naphthyl which may be substituted with ahalogen atom.

In the above-described formulas, X is a bond or a divalent chainhydrocarbon group which may be substituted.

The “divalent chain hydrocarbon group” of the “divalent chainhydrocarbon group which may be substituted” represented by X, may beexemplified by C₁₋₆ alkylene (for example, methylene, ethylene,trimethylene, tetramethylene, etc.), C₂₆ alkenylene (for example,vinylene, propylene, 1- or 2-butenylene, butadienylene, etc.), C₂₋₈alkynylene (for example, ethynylene, 1- or 2-propynylene, 1- or2-butynylene, etc.), or the like.

The substituent which may be carried by the “divalent chain hydrocarbongroup” of the “divalent chain hydrocarbon group which may besubstituted” represented by X, may be exemplified by the same groups asthe substituents which may be carried by the above-described “cyclichydrocarbon group” of the “cyclic hydrocarbon group which may besubstituted” represented by R, and these substituents may substitute 1to 3 of any substitutable positions.

X is, for example, preferably a bond, C₁₋₆ alkenylene or the like, andamong them, a bond is more preferred.

In the above-described formulas, X′ is a bond or —N(R⁵)—, and R⁵ as usedherein may be exemplified by a hydrogen atom, a hydrocarbon group whichmay be substituted, an esterified or amidated carboxyl group, an acylgroup or the like.

The “hydrocarbon group” of the “hydrocarbon group which may besubstituted” represented by R⁵, may be exemplified by alkyl, alkenyl,alkynyl, aryl, cycloalkyl, cycloalkenyl, aralkyl or the like.

For the alkyl, alkenyl, alkynyl, aryl, cycloalkyl and cycloalkenyl,mention may be made of the same groups as the alkyl, alkenyl, alkynyl,aryl, cycloalkyl and cycloalkenyl of the “alkyl which may besubstituted”, “alkenyl which may be substituted”, “alkynyl which may besubstituted”, “aryl which may be substituted”, “cycloalkyl which may besubstituted” and “cycloalkenyl which may be substituted”, respectively,as the substituents for the above-described “cyclic hydrocarbon groupwhich may be substituted” represented by R.

The aralkyl may be exemplified by a C₇₋₁₆ aralkyl group such as aphenyl-C₁₋₆ alkyl group, such as benzyl, phenethyl, 3-phenylpropyl or4-phenylbutyl, a naphthyl-C₁₋₆ alkyl group such as (1-naphthyl)methyl,2-(l-naphthyl)ethyl or 2-(2-naphthyl)ethyl, or the like.

The substituent for the “hydrocarbon group which may be substituted”represented by R⁵, may be exemplified by the same groups as thesubstituents for the above-described “cyclic hydrocarbon group which maybe substituted” represented by R, or the like. Among them, lower alkyl(e.g., C₁₋₆ alkyl such as methyl, ethyl or propyl, etc.), lower alkenyl(e.g., C₂₋₆ alkenyl such as vinyl or allyl, etc.), lower alkynyl (e.g.,C₂₋₆ alkynyl such as ethynyl or propargyl, etc.), amino which may besubstituted, hydroxyl which may be substituted, halogen atom, cyano,amidino which may be substituted, carboxyl, lower alkoxycarbonyl (e.g.,C₁₋₆ alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, etc.),carbamoyl which may be substituted (e.g., carbamoyl which may besubstituted with C₁₋₆ alkyl or acyl (e.g., formyl, C₂₋₆ alkanoyl,benzoyl, C₁₋₆ alkoxycarbonyl which may be halogenated, C₁₋₆alkylsulfonyl which may be halogenated, benzenesulfonyl, etc.), etc.),oxo and the like are preferred, and these substituents may substitute 1to 3 of any substitutable positions.

The “esterified or amidated carboxyl group” represented by R⁵ may beexemplified by the same group as the “esterified or amidated carboxylgroup” as a substituent for the “cyclic hydrocarbon group which may besubstituted” represented by R, or the like.

The acyl group represented by R⁵ may be exemplified by the same group asthe acyl group as a substituent for the “cyclic hydrocarbon group whichmay be substituted” represented by R, or the like.

R⁵ is preferably hydrogen atom, lower alkyl which may be substituted(for example, C₁₋₆ alkyl such as methyl, ethyl or propyl, which may besubstituted with carbamoyl, amino, hydroxyl, halogen atom or the like,etc.), lower alkenyl which may be substituted (for example, C₂₋₆ alkenylsuch as vinyl or allyl, which may be substituted with carbamoyl, amino,hydroxyl, halogen atom or the like, etc.), lower alkynyl which may besubstituted (for example, C₂₋₆ alkynyl such as ethynyl or propargyl,which may be substituted with carbamoyl, amino, hydroxyl, halogen atomor the like, etc.), or the like. Among them, C₁₋₆ alkyl which may besubstituted with a hydrogen atom or carbamoyl (particularly, hydrogenatom) is preferred.

R⁵ may be also bonded to the substituent carried by the divalent chainhydrocarbon group for X, or the substituent for ring A, to form a ring.The ring may be exemplified by the same rings as the below-described“rings” formed by the binding of R² with R¹ or R⁴, and R³ with R⁴, orthe like.

X′ is preferably a bond.

In the above-described formulas, Y is a divalent hydrocarbon group whichmay be substituted (preferably, a divalent chain hydrocarbon group whichmay be substituted).

The “divalent hydrocarbon group” of the “divalent hydrocarbon groupwhich may be substituted” represented by Y, may be exemplified by the“divalent chain hydrocarbon group”, “divalent cyclic hydrocarbon group”,a divalent hydrocarbon group obtained by combination thereof, or thelike.

The “divalent chain hydrocarbon group” may be exemplified by the samegroup as the “divalent chain hydrocarbon group” of the above-described“divalent chain hydrocarbon group which may be substituted” representedby X, or the like.

The “divalent cyclic hydrocarbon group” may be exemplified by the“divalent cyclic hydrocarbon group” formed by eliminating any onehydrogen atom from the “cyclic hydrocarbon group” of the above-described“cyclic hydrocarbon group which may be substituted” represented by R, orthe like. Inter alia, mention may be made of a divalent aryl group,particularly a phenylene group or the like, is preferred, and thephenylene group may be exemplified by 1,2-phenylene, 1,3-phenylene,1,4-phenylene or the like.

The substituent which may be carried by the divalent hydrocarbon groupof the “divalent hydrocarbon group which may be substituted” representedby Y, may be exemplified by the same groups as the substituents for theabove-described “cyclic hydrocarbon group which may be substituted”represented by R, or the like. Among these, lower alkyl (e.g., C₁₋₆alkyl such as methyl, ethyl and propyl, etc.), lower alkenyl (e.g., C₂₋₆alkenyl such as vinyl and allyl, etc.), lower alkynyl (e.g., C₂₋₆alkynyl such as ethynyl and propargyl, etc;), amino which may besubstituted, hydroxyl which may be substituted, cyano, amidino which maybe substituted, carboxyl, lower alkoxycarbonyl (e.g., C₁₋₆alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl, etc.),carbamoyl which may be substituted (e.g., carbamoyl which may besubstituted with C₁₆ alkyl or acyl (e.g., formyl, C₂₋₆ alkanoyl,benzoyl, C₁₋₆ alkoxycarbonyl which may be halogenated, C₁₋₆alkylsulfonyl which may be halogenated, benzenesulfonyl, etc.), etc.),and oxo are preferred, and these substituents may substitute 1 to 3 ofany substitutable positions.

Y is preferably a divalent chain hydrocarbon group which may besubstituted, and inter alia, C₁₋₆ alkylene (particularly, ethylene,etc.) which may be substituted is preferred. Y is preferably C₁₋₃alkylene substituted with hydroxyl.

In the above-described formulas, Y′ is a bond or (═O)— (carbonyl).

Y′ is preferably —(═O)—.

The compound represented by Formula (I) is preferably a compound inwhich X is a bond, X′ is a bond, Y is C₁₋₃ alkylene which may besubstituted (preferably, Y is C₁₋₃ alkylene substituted with hydroxyl),and Y′ is —C(═O)—.

In the above-described formulas, ring A is a nitrogen-containingheterocycle which may be substituted.

For the “nitrogen-containing heterocycle” of the “nitrogen-containingheterocycle which may be substituted” represented by ring A, among thoseexemplified as the “heterocycle” constituting the above-described“heterocyclic group which may be substituted” represented by R, thosecontaining at least one nitrogen atom, and the like, mention may be madeof, for example, nitrogen-containing aromatic heterocycle which containsat least one nitrogen atom as the atom (ring atom) constituting the ringsystem, and which may further contain 1 to 3 (preferably, 1 to 2)heteroatoms of 1 to 3 species (preferably, 1 to 2 species) selected fromoxygen, sulfur and nitrogen atoms and the like; saturated or unsaturatednitrogen-containing non-aromatic heterocycle (nitrogen-containingaliphatic heterocycle); and the like. However, nitrogen-containingaliphatic heterocycle (nitrogen-containing non-aromatic heterocycle) andthe like -are preferred.

The “nitrogen-containing heterocycle” of the “nitrogen-containingheterocycle which may be substituted” represented by ring A ispreferably “monocyclic 5- to 12-membered nitrogen-containingheterocycle”.

For the “nitrogen-containing aliphatic heterocycle”, among thoseexemplified as the “aromatic heterocycle” constituting theabove-described aromatic monocyclic heterocyclic groups and aromaticfused heterocyclic groups represented by R, mention may be made of, forexample, nitrogen-containing aliphatic heterocycle in which part or allof the double bonds of the “nitrogen-containing aromatic heterocycle”containing at least one nitrogen atom are saturated, such as 3- to8-membered (preferably, 5- to 6-membered) saturated or unsaturated(preferably, saturated) monocyclic nitrogen-containing aliphaticheterocycle such as azetidine, pyrrolidine, piperazine, morpholine,thiomorpholine, piperazine, homopiperazine or the like. Among them,piperazine, piperidine and the like are preferably used.

The substituent which may be carried by the “nitrogen-containingheterocycle” of the “nitrogen-containing heterocycle which may besubstituted” represented by ring A, may be exemplified by the samegroups as the substituents which may be carried by the “heterocyclicgroup” of the above-described “heterocyclic group which may besubstituted” represented by R, and these substituents may substitute 1to 5 (preferably, 1 to 3) of any substitutable positions.

Ring A is preferably a piperazine ring which may be substituted or apiperidine ring which may be substituted, and among these, the formulain Formula (I):

is preferably the formula:

wherein ring A′ may be further substituted, or the formula:

wherein ring A″ may be further substituted.

In the above-described formulas, Z¹ and Z³ are each independently a bondor a divalent chain hydrocarbon group which may be substituted.

The “divalent chain hydrocarbon group” of the “divalent chainhydrocarbon group which may be substituted” represented by Z¹ and Z³,respectively, may be exemplified by the same group as the “divalentchain hydrocarbon group” of the “divalent chain hydrocarbon group whichmay be substituted” represented by X, or the like.

The substituents for the “divalent chain hydrocarbon group which may besubstituted” represented by Z¹ and Z³, respectively, may be exemplifiedby the same groups of the same number as the substituents for the“divalent chain hydrocarbon group which may be substituted” representedby X, or the like.

Z¹ and Z³ are each preferably a bond, or C₁₋₆ alkylene such asmethylene, ethylene, trimethylene or tetramethylene, or the like.

In the above-described formulas, Z2 is a bond or —N(R⁶)—, wherein R⁶ isa hydrogen atom, a hydrocarbon group which may be substituted, or anacyl group.

The “hydrocarbon group” of the “hydrocarbon group which may besubstituted” represented by R⁶, may be exemplified by the same group asthe “hydrocarbon group” of the above-described “hydrocarbon group whichmay be substituted” represented by R⁵, or the like.

The substituent for the “hydrocarbon group which may be substituted”represented by R⁶, may be exemplified by the same groups of the samenumber as the substituents for the above-described “hydrocarbon groupwhich may be substituted” represented by R⁵, or the like.

The acyl group represented by R⁶ may be exemplified by the same group asthe acyl group represented by R⁵, or the like.

Z² is preferably a bond or the like.

The compound represented by Formula (I) is preferably a compound inwhich Z¹ and Z² are each a bond, and Z³ is C₁₋₃ alkylene which may besubstituted.

In the above-described formulas, B is a group represented by theformula:

wherein R¹ and R² are each independently a hydrogen atom, a halogenatom, a hydrocarbon group which may be substituted, an alkoxy groupwhich may be substituted, a carboxyl group which may be esterified oramidated, an acyl group, or an amino group which may be substituted; R³is a hydrogen atom, a hydrocarbon group which may be substituted, acarboxyl group which may be esterified or amidated, or an acyl group; R⁴is a hydrocarbon group which may be substituted; and R² and R¹ or R⁴,and R³ and R⁴ may be respectively bonded to each other to form a ringwhich may be substituted.

The “hydrocarbon group” of the “hydrocarbon group which may besubstituted” represented by R¹, R², R³ and R⁴, respectively, may beexemplified by the same group as the “hydrocarbon group” of the“hydrocarbon group which may be substituted” represented by R⁵, or thelike, and the substituents which may be carried by the “hydrocarbongroup” may be exemplified by the same groups of the same number as thesubstituents for the above-described “hydrocarbon group which may besubstituted” represented by R⁵, or the like.

The alkoxy group of the “alkoxy group which may be substituted”represented by R¹ or R², may be exemplified by a C₁₋₆ lower alkoxy group(e.g., methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,isopropoxy, etc.).

The substituents which may be carried by the alkoxy group of the “alkoxygroup which may be substituted” represented by R¹ or R², may beexemplified by the same groups of the same number as the substituentsfor the above-described “hydrocarbon group which may be substituted”represented by R⁵, or the like.

The acyl group represented by R¹, R² or R³ may be exemplified by thesame group as the acyl group as a substituent for the “cyclichydrocarbon group which may be substituted” represented by R, or thelike.

The “carboxyl group which may be esterified or amidated” represented byR¹, R² or R³, may be exemplified by the same group as the “carboxylwhich may be esterified or amidated” as a substituent for theabove-described “cyclic hydrocarbon group which may be substituted”represented by R, or the like.

The “ring” of the “ring which may be substituted” which may be formed byR² and R¹ or R⁴, and R³ and R⁴, respectively, by binding to each other,may be either homocycle or heterocycle.

Examples of the “homocycle or heterocycle” include (i) aromaticheterocycle or non-aromatic heterocycle containing preferably 1 to 3heteroatoms of 1 or 2 species selected from nitrogen, sulfur and oxygenatoms in addition to carbon atoms, and (2) cyclic hydrocarbon(homocycle) consisting of carbon atoms, and the like.

The “aromatic heterocycle” may be exemplified by a 5- to 6-memberedaromatic heterocycle containing 1 to 3 heteroatoms selected fromnitrogen, oxygen and sulfur atoms in addition to carbon atoms (forexample, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole,pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole,isoxazole ring, etc.), or the like.

The “non-aromatic heterocycle” may be exemplified by a 5- to 9-membered(preferably, 5- or 6-membered) non-aromatic heterocycle containing 1 to3 heteroatoms selected from nitrogen, oxygen and sulfur atoms inaddition to carbon atoms (for example, tetrahydropyridine,dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine,tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydrothiophene,dihydrofuran, piperidine, piperazine, hexahydropyrimidine,hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine,pyrazoline, imidazolidine, thiazoline, isothiazoline, oxazoline,isoxazoline, pyrazolidine, tetrahydrothiophene, tetrahydrofuran,tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole,tetrahydroisoxazole ring, etc.), or the like.

The “cyclic hydrocarbon (homocycle)” may be exemplified by a 3- to10-membered (preferably, 5- to 9-membered, more preferably 5- or6-membered) cyclic hydrocarbon, or the like, for example, benzene, C₃₋₁₀cycloalkene (for example, cyclobutene, cyclopentene, cyclohexene,cycloheptene, cyclooctene, etc.), C₃₋₁₀ cycloalkane (for example,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane,etc.), or the like. The cycloalkene is preferably C₅₋₆ cycloalkene (forexample, cyclopentene, cyclohexene, etc.), or the like, while thecycloalkane is preferably C₅₋₆ cycloalkane (for example, cyclohexane,cyclopentane, etc.), or the like.

The “ring” which is formed by R² and R¹ or R⁴, and R³ and R⁴ by bindingto each other is preferably, for example, a 5- to 9-membered(preferably, 5- or 6-membered) non-aromatic heterocycle-containing 1 to2 (preferably, two) nitrogen atoms in addition to carbon atoms, andinter alia, tetrahydropyridine, tetrahydropyrazine, tetrahydropyrrole,tetrahydroimidazole and the like may be mentioned as preferred examples.

The substituents for the “ring which may be substituted” which is formedby R² and R¹ or R⁴, and R³ and R⁴ by binding to each other, may beexemplified by the same groups as the substituents for theabove-described “heterocyclic group which may be substituted”represented by R, or the like, and these substituents may substitute 1to 5 (preferably, 1 to 3) of any substitutable positions. Thesubstituent for the “ring which may be substituted” is, inter alia,preferably a C₁₋₆ alkyl group, a hydroxyl group, an oxo group, or thelike.

R⁶ may be bonded to R¹, R², R³ or R⁴ to form a ring which may besubstituted, and the ring may be exemplified by the same ring as the“ring” formed by R² and R¹ or R⁴ by binding to each other, or the like.The substituents for the “ring which may be substituted” may beexemplified by the same groups as the substituents for theabove-described “heterocyclic group which may be substituted”represented by R, and these substituents may substitute 1 to 5(preferably, 1 to 3) of any substitutable positions.

In the above-described formulas, a is 0, 1 or 2 (preferably, 2).

For the compound represented by Formula (I),N-(4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-i,3-thiazol-2(3H)-ylidene)-N-methylamine,4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-imine,N-(5-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine,5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-imine,and2-(2-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)imino)-1,3-thiazol-3(2H)-yl)ethanoland the like, and salts thereof are preferably used.

The salt of the compound represented by Formula (I) may be exemplifiedby a pharmaceutically acceptable salt or the like, for example, an acidaddition salt with an acid such as trifluoroacetic acid, acetic acid,lactic acid, succinic acid, maleic acid, tartaric acid, citric acid,gluconic acid, ascorbic acid, benzoic acid, methanesulfonic acid,p-toluenesulfonic acid, cinnamic acid, fumaric acid, phosphonic acid,hydrochloric acid, nitric acid, hydrobromic acid, hydroiodic acid,sulfamic acid, sulfuric acid or the like; a salt with metal such assodium, potassium, magnesium, calcium or the like; an organic salt suchas tromethamine, t-butylamine, trimethylamine, triethylamine, pyridine,picoline, N-methylpyrrolidine, N-methylpiperidine, N-methylmorpholine orthe like; or the like.

When an optically active form of Compound (I) is needed, for example, anoptically active form can be obtained by using an optically activestarting material, or by resolving a racemate of the compound usingconventional methods.

A prodrug of Compound (I) refers to a compound which is converted toCompound (I) by an in vivo reaction caused by an enzyme, gastric acid orthe like under physiological conditions, that is, a compound which isconverted to Compound (I) upon occurrence of enzymatic oxidation,reduction, hydrolysis or the like, or a compound which is converted toCompound (I) upon occurrence of hydrolysis or the like by gastric acidor the like. The prodrug of Compound (I) may be exemplified by compoundsresulting from acylation, alkylation or phosphorylation of the aminogroup of Compound (I) (for example, the compounds in which the aminogroup of Compound (I) is in the form of eicosanoyl, alanyl,pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl,tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, tert-butyl orthe like); compounds resulting from acylation, alkylation,phosphorylation or boration of the hydroxyl group of Compound (I) (forexample, the compounds in which the hydroxyl group of Compound (I) is inthe form of acetyl, palmitoyl, propanoyl, pivaloyl, succinyl, fumaryl,alanyl, dimethylaminomethylcarbonyl or the like); compounds resultingfrom esterification or amidation of the carboxyl group of Compound (I)(for example, the compounds in which the carboxyl group of Compound (I)is in the form of ethyl ester, phenyl ester, carboxymethyl ester,dimethylaminomethyl ester, pivaloyloxymethyl ester,ethoxycarbonyloxyethyl ester, phthalidyl ester,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester,cyclohexyloxycarbonylethyl ester, methylamide or the like); or the like.These compounds can be prepared from Compound (I) by methods known perse in the art.

Furthermore, the prodrug of Compound (I) may be also a compound which isconverted to Compound (I) under physiological conditions, as describedin “Development of Pharmaceutical Products”, Vol. 7, Design ofMolecules, Hirokawa Publisher, pp. 163-198 (1990).

Also, Compound (I) may be labeled with isotopes (for example, ³H, ¹⁴C,^(35 S,) ¹²⁵I, etc.)

Compound (I) can be prepared by, for example, the following methods A toG. Each of the compounds described in the following reaction scheme maybe in a salt form as long as the reaction is not adversely affected, andsuch salt may be exemplified by the same ones as the salts of thecompound represented by Formula (I), or the like.

Method A

Compound (I′) can be prepared by reacting Compound (IV) represented byFormula (IV):L¹-Z¹-Z² ³-Z-Bwherein L¹ is a leaving group (for example, a halogen atom (e.g.,fluorine, chlorine, bromine, iodine, etc.), or a group forming areactive derivative of sulfonic acid (e.g., sulfonic acid ester, activesulfonic acid amide (e.g., 1,2,4-triazolide, imidazolide, etc.),quaternary aminesulfonyl product (e.g., N-methylpyrrolidinium salt,etc.), bis-sulfonylimide (e.g., N-phenylbis-sulfonylimide, etc.), etc.),or the-like)-, and the-other symbols have the meanings as defined above,or a salt thereof with Compound (III) represented by Formula (III):

wherein ring A′″ is a nitrogen-containing heterocycle which may besubstituted, containing at least two nitrogen atoms as the ring atom,and the other symbols have the meanings as defined above, or a saltthereof. The salt of Compound (III) or Compound (IV) may be exemplifiedby the acid addition salts with the above-described acids that form acidaddition salts with Compound (I).

The present reaction is in general carried out in a solvent, and asolvent which does not obstruct the reaction is appropriately selected.For such solvent, alcohols (e.g., methanol, ethanol, propanol,isopropanol, butanol, tert-butanol, etc.), ethers (e.g., dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether, ethylene glycol-dimethyl ether, ethylene glycol-monomethyl ether,etc.), esters (e.g., ethyl formate, ethyl acetate, n-butyl acetate,etc.), carboxylic acids (e.g., formic acid, acetic acid, propionic acid,etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform,carbon tetrachloride, trichloroethylene, 1,2-dichloroethane,chlorobenzene, etc.), hydrocarbons (e.g., n-hexane, benzene, toluene,etc.), amides (e.g., formamide, N,N-dimethylformamide,N,N-dimethylacetamide, etc.), ketones (e.g., acetone, methyl ethylketone, methyl isobutyl ketone, etc.), nitrites (e.g.,.acetonitrile,propionitrile, etc.) and the like, as well as dimethyl sulfoxide,sulfolane, hexamethyl phosphoramide, water and the like are usedindividually or as mixed solvents.

The present reaction may be carried out in the presence of base, ifnecessary, and such base may be exemplified by inorganic bases such aslithium hydroxide, potassium hydroxide, sodium hydroxide, calciumhydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogen carbonate or the like; alkali metal saltsof C₁₋₆ lower fatty acid such as sodium formate, sodium acetate,potassium acetate or the like; or tertiary amines such as triethylamine,tri(n-propyl)amine, tri(n-butyl)amine, diisopropylethylamine,cyclohexyldimethylamine, pyridine, lutidine, γ-collidine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine or the like.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (IV) with respect to Compound (III).

The reaction temperature is -20 to 200° C., preferably 0 to 170° C.

The reaction time may vary depending on the type of Compound (III) orCompound (IV), type of solvent, reaction temperature or the like, but isusually about 1 minute to about 72 hours, preferably about 15 minutes toabout 24 hours.

Method B

Compound (I″) can be prepared by reacting Compound (IV′) represented byFormula (IV′):

wherein R⁶′ is a straight-chained hydrocarbon group which may besubstituted, and the other symbols have the meanings as defined above,or a salt thereof with Compound (III) or a salt thereof. The salt ofCompound (IV′) or Compound (III) may be exemplified by the acid additionsalts with the above-described acids forming acid addition salts withCompound (I).

In the present method, Compound (I″) can be prepared by forming an iminefrom Compound (IV′) or a salt thereof and Compound (III) or a saltthereof, and then reducing the imine. Formation of the imine may becarried out in the presence of an acid catalyst, if necessary, and suchacid catalyst may be exemplified by hydrochloric acid, sulfuric acid,carboxylic acids (e.g., formic acid, acetic acid, propionic acid, etc.),sulfonic acids (methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, etc.),or the like, while the reducing agent may be exemplified by NaBH₄,LiBH₄, or the like. The present method is also applicable to thepreparation of Compound (I″) by reacting Compound (IV′) or a saltthereof and Compound (III) or a salt thereof (an inorganic salt, anorganic salt, etc.), in the presence of the above-mentioned acid, usingNaBH(OAc)₃ or NaCNBH₃.

The present reaction is in general carried out in a solvent, and asolvent which does not obstruct the reaction is appropriately selected.For such solvent, alcohols (e.g., methanol, ethanol, propanol,isopropanol, butanol, tert-butanol, etc.), ethers (e.g., dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether, ethylene glycol-dimethyl ether, ethylene glycol-monomethyl ether,etc.), esters (e.g., ethyl formate, ethyl acetate, n-butyl acetate,etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform,carbon tetrachloride, trichloroethylene, 1,2-dichloroethane,chlorobenzene, etc.), hydrocarbons (e.g., n-hexane, benzene, toluene,etc.), amides (e.g., formamide, N,N-dimethylformamide,N,N-dimethylacetamide, etc.), nitriles (e.g., acetonitrile,propionitrile, etc.) and the like, as well as dimethyl sulfoxide,sulfolane, hexamethyl phosphoramide, water and the like are usedindividually or as mixed solvents.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (IV′) with respect to Compound (III).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (III) orCompound (IV′), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method C

Compound (I′″) can be prepared by reacting Compound (V) represented byFormula (V):R—X—S(O)_(a)—X′—Y—COOHwherein the symbols have the same meanings as defined above,

or a salt thereof with Compound (II) represented by Formula (II):

wherein the symbols have the same meanings as defined above.

The present method is carried out by reacting Compound (II) or a saltthereof with-free acid (V) or a salt thereof (an inorganic salt, anorganic salt, etc.) or a reactive derivative thereof (for example, acidhalide, ester, acid azide, acid anhydride, mixed acid anhydride, activeamide, active ester, active thioester, etc.). The salt of Compound (II)may be exemplified by the acid addition salts with the above-describedacids forming acid addition salts with Compound (I).

The inorganic salt used for Compound (V) may be exemplified by alkalimetal salts (for example, sodium salts, potassium salts, etc.), alkalineearth metal salts (for example, calcium salts, etc.), while the organicsalts may be exemplified by trimethylamine salts, triethylamine salts,tert-butyldimethylamine salts, dibenzylmethylamine salts,benzyldimethylamine salts, N,N-dimethylaniline salts, pyridine salts,quinoline salts or the like. The acid halide may be exemplified by acidchloride, acid bromide or the like, while the ester may be exemplifiedby lower alkyl esters such as methyl, ethyl or the like. The mixed acidanhydride may be exemplified by mono-C₁₋₄ alkyl carbonate mixed acidanhydrides (for example, mixed acid anhydrides such as free acid (V)with monomethyl carbonate, monoethyl carbonate, monoisopropyl carbonate,monoisobutyl carbonate, mono-tert-butyl carbonate, monobenzyl carbonate,mono(p-nitrobenzyl) carbonate, monoallyl carbonate or the like), C₁₋₆aliphatic carboxylic acid mixed acid anhydrides (for example, mixed acidanhydrides such as free acid (V) with acetic acid, cyanoacetic acid,propionic acid, butyric acid, isobutyric acid, valeric acid, isovalericacid, pivalic acid, trifluoroacetic acid, trichloroacetic acid,acetoacetic acid or the like), C₇₋₁₁ aromatic carboxylic acid mixed acidanhydrides (for example, free acid (V) with benzoic acid, p-toluyl acid,p-chlorobenzoic acid or the like), organic sulfonic acid mixed acidanhydrides (for example, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid or the like), or the like.The active amide may be exemplified by an amide with anitrogen-containing heterocyclic compound (for example, acid amides suchas free acid (V) with pyrazole, imidazole, benzotriazole, or the likeand these nitrogen-containing heterocyclic compounds may be substitutedwith C₁₋₆ alkyl (for example, methyl, ethyl propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, etc.), C₁₋₆ alkoxy (for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.),halogen atom (for example, fluorine, chlorine, bromine, etc.), oxo,thioxo, C₁₋₆ alkylthio (for example, methylthio, ethylthio, propylthio,butylthio, etc.), etc.).

The active ester may be exemplified by organic phosphoric acid esters(for example, diethoxyphosphoric acid ester, diphenoxyphosphoric acidester, etc.), as well as p-nitrophenyl ester, 2,4-dinitrophenyl ester,cyanomethyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester,6-chloro-1-hydroxybenzotriazole ester, 1-hydroxy-1H-2-pyrridone ester,or the like. The active thioester may be exemplified by esters ofaromatic heterocyclic thiol compounds [these heterocycles may besubstituted with C₁₋₆ alkyl (for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), C₁₋₆ alkoxy(for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,etc.), halogen atom (for example, fluorine, chlorine, bromine, etc.),C₁₋₆ alkylthio (for example, methylthio, ethylthio, propylthio,butylthio, etc.), or the like] [e.g., 2-pyridylthiol ester,2-benzothiazolylthiol ester], or the like.

The present reaction is in general carried out in a solvent, and ifnecessary, is carried out in the presence of base or a condensing agent(e.g., carbodiimide (DCC, WSC, DIC, etc.), phosphoric acid derivative(e.g., diethyl cyanophosphate, DPPA, BOP-Cl, etc.),4-(4,6-dimethoxy-1,3-5-triazin-2-yl)-4-methylmorpholinium chloride(DMTMM: Kunishima, et al., Tetrahedron, 1999, 55, 13159), etc.). Forsuch solvent, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether,tert-butyl methyl ether, diisopropyl ether, - ethylene glycol-dimethylether, etc.), esters (e.g.-, ethyl formate, ethyl acetate, n-butylacetate, etc.), halogenated hydrocarbons (e.g., dichloromethane,chloroform, carbon tetrachloride, trichloroethylene, 1,2-dichloroethane,chlorobenzene, etc.), hydrocarbons (e.g., n-hexane, benzene, toluene,etc.), amides (e.g., formamide, N,N-dimethylformamide,N,N-dimethylacetamide, etc.), nitriles (e.g., acetonitrile,propionitrile, etc.), as well as sulfolane, hexamethylphosphoramide,water and the like are used individually or as mixed solvents. For thebase, the bases listed for the above-described Method A are used.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (II) with respect to Compound (V).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (V) orCompound (II), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method D

Compound (I″″) can be prepared by reacting Compound (VI) represented byFormula (VI):R—X—S(O)_(a)—X′—Y-L²wherein L² is the same leaving group as L¹ of Formula (IV), and theother symbols have the same meanings as defined above, or a salt thereofwith Compound (II) or a salt thereof.

The reaction of the present method is carried out in general in asolvent, and a solvent which does not obstruct the reaction isappropriately selected. For such solvent, the same solvents as thoselisted for the above-described Method A are used.

The present reaction may be carried out in the presence of base, and thebase may be exemplified by alkali metal hydrides such as potassiumhydride, sodium hydride, or the like; metal alkoxides having 1 to 6carbon atoms such as lithium ethoxide, lithium tert-butoxide, sodiummethoxide, sodium ethoxide, potassium tert-butoxide or the like;inorganic bases such as lithium hydroxide, potassium hydroxide, sodiumhydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate or the like; or tertiary amines such as triethylamine,tri(n-propyl)amine, tri(n-butyl)amine, diisopropylethylamine,cyclohexyldimethylamine, pyridine, lutidine, γ-collidine,N,N-dimethylaniline, N-methylpiperidine, N-methylpyrrolidine,N-methylmorpholine or the like.

The reaction is carried out by using 0.5 to 10 equivalents, preferably0.8 to 3-equivalents, of Compound (II) with respect to Compound (VI).

The reaction temperature is −30 to 250° C., preferably −10 to 150° C.

The reaction time may vary depending on the type of Compound (VI) orCompound (II), type of solvent, reaction temperature or the like, but isusually about 1 minute to 72 hours, preferably about 15 minutes to about24 hours.

Method E

A compound in which a is 1 or 2 with respect to Formula (I) can beprepared by oxidizing Compound (Ia) represented by Formula (Ia):

wherein the symbols have the meanings as defined above, or a saltthereof.

The oxidation reaction is carried out in the presence of an oxidizingagent. Here, the oxidizing agent may be exemplified by oxygen, hydrogenperoxide, an organic peracid such as perbenzoic acid, m-chloroperbenzoicacid, peracetic acid or the like; a perchlorate such as lithiumperchlorate, silver perchlorate, tetrabutylammonium perchlorate or thelike; a periodate such as odium periodate or the like; periodic acid;manganese dioxide; lead tetraacetate; a permanganate such as potassiumpermanganate or the like; halogen such as iodine, bromine, chlorine orthe like; N-bromosuccinic acid imide, N-chlorosuccinic acid imide,sulfuryl chloride, chloramine T, or the like.

The present reaction is in general carried out in a solvent, and asolvent which does not obstruct the reaction is appropriately selected.For such solvent, alcohols (e.g., methanol, ethanol, propanol,isopropanol, butanol, tert-butanol, etc.), ethers (e.g., dioxane,tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropylether, ethylene glycol-dimethyl ether, etc.), esters (e.g., ethylformate, ethyl acetate, n-butyl acetate, etc.), carboxylic acids (e.g.,formic acid, acetic acid, propionic acid, etc.), halogenatedhydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride,trichloroethylene, 1,2-dichloroethane, chlorobenzene, etc.),hydrocarbons (e.g., n-hexane, benzene, toluene, etc.), amides (e.g.,formamide, N,N-dimethylformamide, N,N-dimethylacetamide, etc.), ketones(e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.),nitrites (e.g., acetonitrile, propionitrile, etc.) and the like, as wellas sulfolane, hexamethyl phosphoramide, water and the like are usedindividually or as mixed solvents.

The present reaction can be carried out in the presence of base. Forsuch base, inorganic bases such as, for example, alkali metal hydroxidessuch as lithium hydroxide, sodium hydroxide, potassium hydroxide and thelike; alkali earth metal hydroxides such as magnesium hydroxide, calciumhydroxide and the like; alkali metal carbonates such as sodiumcarbonate, potassium carbonate and the like; alkali metal hydrogencarbonates such as sodium hydrogen carbonate, potassium hydrogencarbonate and the like are used.

The reaction is carried out by using 0.1 to 20 equivalents, preferablyabout 0.4 to 10 equivalents, of the oxidizing agent, and 0.1 to 20equivalents, preferably 0.4 to 10 equivalents of the base, with respectto Compound (Ia).

The present reaction may be carried out in the presence of acid, ifnecessary, and for such acid, mineral acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, perchloric acid andthe like; sulfonic acids such as methanesulfonic acid, ethanesulfonicacid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acidand the like; and organic acids such as formic acid, acetic acid,propionic acid, trifluoroacetic acid and the like are used. The amountof use for these acids is 0.1 to 20 equivalents, preferably 0.5 to 10equivalents, with respect to Compound (Ia).

The reaction temperature is about −10° C. to about 250° C., preferablyabout −5° C. to about −150° C.

The reaction time may vary depending on the type of Compound (Ia), typesof solvent and base, reaction temperature or the like, but is usuallyabout 1 minute to about 50 hours, preferably about 5 minutes to about 24hours.

Method F

Compound (I) can be prepared by reacting Compound (VII) represented byFormula (VII):

wherein B′ is a group represented by the formula:

(wherein the symbols have the meanings as defined above), and the othersymbols have the meanings as defined above, with Compound (VIII)represented by Formula (VIII):L³-R⁴wherein L³ is a leaving group (for example, a halogen atom (e.g.,fluorine, chlorine, bromine, iodine, etc.), a C₁₋₆ alkylsulfonyloxygroup which may be substituted with 1 to 3 halogen atoms (e.g.,methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy,etc.), an arylsulfonyloxy group which may be substituted (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy, etc.),or the like; and the other symbols have the meanings as defined above.

The present method is carried out by reacting Compound (VII) withCompound (VIII).

The present reaction is in general carried out in a solvent, and asolvent which does not obstruct the reaction is appropriately selected.For such solvent, the same ones as the solvents listed for theabove-described method D, and the like are used.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (VIII) with respect to Compound (VII).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (VII) orCompound (VIII), types of solvent and base, reaction temperature, or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method G

Compound (I) can be prepared by reacting Compound (IX) represented byFormula (IX):R—X—S(O)_(a)Mwherein M is a hydrogen atom, an alkali metal, an alkaline earth metalor a leaving group (for example, a halogen atom (e.g., fluorine,chlorine, bromine, iodine, etc.), and the other symbols have themeanings as defined above, or a salt thereof with a compound representedby Formula (X):

wherein X″ is alkenyl or alkynyl (preferably, C₂₋₈ alkenyl or C₂₋₈alkynyl) in which the carbon atom at the remotest position from thecarbon atom bound to Y has an unsaturated bonds, or alkyl (preferably,C₁₋₈ alkyl) in which the carbon atom at the remotest position from thecarbon atom bound to Y has a leaving group (e.g., a halogen atom (e.g.,fluorine, chlorine, bromine, iodine, etc.), a C₁₋₆ alkylsulfonyloxygroup which may be substituted with 1 to 3 halogen atoms (e.g.,methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy,etc.), an arylsulfonyloxy group which may be substituted (e.g.,benzenesulfonyloxy, p-toluenesulfonyloxy, p-bromobenzenesulfonyloxy,etc.), a hydroxyl group, etc.); and the other symbols have the meaningsas defined above.

The present method is in general carried out in a solvent, and ifnecessary, is carried out in the presence of base. For such solvent andbase, the same ones as the solvents and bases mentioned for theabove-described Method A are used.

The reaction is carried out by using 0.5 to 3 equivalents, preferably0.8 to 2 equivalents, of Compound (IX) with respect to Compound (X).

The reaction temperature is −50 to 150° C., preferably −20 to 120° C.

The reaction time may vary depending on the type of Compound (IX) orCompound (X), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 24 hours.

The starting material compounds used in each of the above reactions canbe synthesized by, for example, the following methods.

Method H

A compound in which Y′ is —(C═O)— with respect to Formula (XIV):

wherein the symbols have the meanings as defined above, is prepared byreacting Compound (XI) represented by Formula (XI):

wherein P¹ is a protective group for imino group, and the other symbolshave the meanings as defined above, or a salt thereof with Compound(XII) represented by Formula (XII):X″—Y—COOHwherein the symbols have the meanings as defined above, or a saltthereof.

For the protective group for imino group represented by P¹, formyl, C₁₋₆alkylcarbonyl (for example, acetyl, propionyl, etc.), benzoyl, C₁₋₆alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl,tert-butoxycarbonyl (Boc), etc.), allyloxycarbonyl (Aloc),phenoxycarbonyl, fluorenylmethyloxycarbonyl (Fmoc), C₇₋₁₀aralkylcarbonyl (for example, benzylcarbonyl, etc.), C₇₋₁₀aralkyloxycarbonyl (for example, benzyloxycarbonyl (Z), etc.), C₇₋₁₀aralkyl (for example, benzyl, etc.), trityl, phthaloyl,N,N-dimethylaminomethylene and the like, which may be respectivelysubstituted, are used. For their substituents, a phenyl group, a halogenatom (for example, fluorine, chlorine, bromine, iodine, etc.), a C₁₋₆alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl,butylcarbonyl, etc.), a nitro group and the like are used, and thenumber of substituents is from about 1 to 3.

The present method can be carried out by the same method as theabove-described Method C.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XII) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (XII), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method I

A compound in which Y′ is a bond with respect to Formula (XIV):

wherein the symbols have the meanings as defined above, is prepared byreacting Compound (XI) or a salt thereof with Compound (XIII)represented by Formula (XIII):X″—Y-L²wherein the symbols have the meanings as defined above, or a saltthereof.

The present method can be carried out by the same method as theabove-described Method D.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XIII) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (XIII), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method J

A compound in which Y′ is —(C═O)— with respect to Formula (XV):

wherein the symbols have the meanings as defined above, is prepared byreacting Compound (XI) or a salt thereof with Compound (V) representedby Formula (V):R—X—S(O)_(a)—X′—Y—COOHwherein the symbols have the meanings as defined above, or a saltthereof.

The present method can be carried out by the same method as theabove-described Method C.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (V) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (V), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method K

A compound in which Y′ is a bond with respect to Formula (XV):

wherein the symbols have the meanings as defined above, is prepared byreacting Compound (XI) or a salt thereof with Compound (VI) representedby Formula (VI):R—X—S(O)_(a)—X—Y-L²wherein the symbols have the meanings as defined above, or a saltthereof.

The present method can be carried out by the same method as theabove-described Method D.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (VI) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (VI), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method L

Compound (XV) represented by Formula (XV):

wherein the symbols have the meanings as defined above, is prepared byreacting Compound (XIV) or a salt thereof with Compound (IX) representedby Formula (IX):R—X—S(O)_(a)-Mwherein the symbols have the meanings as defined above, or a saltthereof.

The present method can be carried out by the same method as theabove-described Method G.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (IX) with respect to Compound (XIV).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XIV) orCompound (IX), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method M

Compound (III) represented by Formula (III):

wherein the symbols have the meanings as defined above, or a saltthereof can be prepared by eliminating the protective group (p¹) forimino group from Compound (XV) or a salt thereof.

The method of eliminating the protective group for imino group can becarried out according to, for example, the method described in T. W.Green et al., “Protective Groups in Organic Synthesis”, John Wiley &Sons, Inc., New York, or a method equivalent thereto. For example,methods of using acid, base, reduction, ultraviolet ray, palladiumacetate and the like are used.

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XV), typesof solvent and base, reaction temperature or the like, but is usuallyabout 1 minute to about 100 hours, preferably about 15 minutes to about48 hours.

Method L′

Compound (XVI) represented by Formula (XVI):R—X—S(O)_(a)—X′—Y-L³wherein the symbols have the meanings as defined above, is prepared byreacting Compound (IX) represented by Formula (IX):R—X—S(O)_(a)-Mwherein the symbols have the meanings as defined above, or a saltthereof with Compound (XIII′) represented by Formula (XIII′):X″—Y-L³wherein L³ is a functional group which can be derived into a carboxylgroup (for example, alkoxycarbonyl, cyano, carbamoyl which may besubstituted, etc.), and the other symbols have the meanings as definedabove, or a salt thereof.

The present method can be carried out by the same method as theabove-described Method G.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XIII′) with respect to Compound (IX).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (IX) orCompound (XIII′), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method N

Compound (V) represented by Formula (V):R—X—S(O)_(a)—X′—Y—COOHwherein the symbols have the meanings as defined above, is prepared fromCompound (XVI) represented by Formula (XVI):R—X—S(O)_(a)—X′—Y-L³wherein the symbols have the meanings as defined above, or a saltthereof.

In the present method, L³ (a functional group which can be derived intoa carboxyl group) is subjected to a reaction such as acid hydrolysis(e.g., hydrochloric acid, hydrobromic acid, sulfuric acid or the like isused), alkali hydrolysis (e.g., sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium carbonate, potassium carbonate, sodiumhydrogen carbonate or the like is used), or the like. In addition, thereaction solvent, reaction time, reaction temperature and reaction timeare set according to the reaction solvent, reaction time, reactiontemperature and reaction time described in Method A, or a methodequivalent thereto.

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XVI),types of solvent and base, reaction temperature or the like, but isusually about 1 minute to about 100 hours, preferably about 15 minutesto about 48 hours.

Method O

Compound (XVIII) represented by Formula (XVIII):R—X—S(O)_(a)—X′—Y—COOP²wherein the symbols have the meanings as defined above, is prepared byreacting Compound (IX) or a salt thereof with Compound (XVII)represented by Formula (XVII):X″—Y—COOP²wherein P² is C₁₋₆ alkyl (for example, methyl, ethyl, propyl,tert-butyl, allyl, etc.) or aralkyl (benzyl, phenethyl, etc.) or thelike, and the other symbols have the meanings as defined above, or asalt thereof.

The present method can be carried out by the same method as theabove-described Method G.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XVII) with respect to Compound (IX).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (IX) orCompound (XVII), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method P

Compound (V) or a salt thereof can be prepared by hydrolyzing Compound(XVIII) or a salt thereof, or the like.

In the present method, the hydrolysis of ester COOP² is carried out by areaction such as acid hydrolysis (e.g., hydrochloric acid, hydrobromicacid, sulfuric acid or the like is used), alkali hydrolysis (e.g.,sodium hydroxide, potassium hydroxide, lithium hydroxide, sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate or the like isused), or the like. In addition, the reaction solvent, reaction time,reaction temperature and reaction time are set according to the reactionsolvent, reaction time, reaction temperature and reaction time describedin Method A, or a method equivalent thereto.

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XVIII),types of solvent and base, reaction temperature or the like, but isusually about 1 minute to about 100 hours, preferably about 15 minutesto about 48 hours.

Method Q

Compound (XIX) represented by Formula (XIX):

wherein the symbols have the meanings as defined above, is prepared byreacting Compound (XI) or a salt thereof with Compound (IV) or a saltthereof.

The present method can be carried out by the same method as theabove-described Method A.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (IV) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (IV), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method R

A compound in which Z¹ is —CH(R⁶′)— and Z² is a bond with respect toFormula (XIX), is prepared by reacting Compound (XI) or a salt thereofwith Compound (IV′) or a salt thereof.

The present method can be carried out by the same method as theabove-described Method B.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (IV′) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (IV′), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method 5

Compound (XIX′) represented by Formula (XIX′):

wherein the symbols have the meanings as defined above, is prepared byreacting Compound (XI) or a salt thereof with Compound (IV″) representedby Formula (IV″):L¹-Z¹-Z²Z-B′wherein the symbols have the meanings as defined above, or a saltthereof.

The present method can be carried out by the same method as theabove-described Method A.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (IV″) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (IV″), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method T

A compound in which Z¹ is —CH(R⁶′)— and Z² is a bond with respect toFormula (XIX′), is prepared by reacting Compound (XI) or a salt thereofwith Compound (IV′″) represented by Formula (IV′″):

wherein the symbols have the meanings as defined above, or a saltthereof.

The present method can be carried out by the same method as theabove-described Method B.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (IV′″) with respect to Compound (XI).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XI) orCompound (IV′″), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method U

Compound (XIX) or a salt thereof can be prepared by reacting Compound(XIX′) or a salt thereof with Compound (VIII).

The reaction conditions, reaction solvent, reaction time and the likefor the present reaction are set according to the reaction conditionsand the like described for the reaction between Compound (VII) andCompound (VIII) according to Method F, or a method equivalent thereto.

Method V

Compound (XX) represented by Formula (XX):

wherein the symbols have the meanings as defined above, or a saltthereof can be prepared by eliminating the protective group (P¹) on thenitrogen atom constituting ring A of Compound (XIX) or a salt thereof.

The reaction conditions, reaction solvent, reaction time and the likefor the present reaction are set according to the reaction conditionsand the like described for the deprotection reaction for Compound (XV)according to Method M, or a method equivalent thereto.

Method H′

A compound in which Y′ is —(C═O)— with respect to Formula (X) isprepared by reacting Compound (II) or a salt thereof with Compound (XII)or a salt thereof.

The present method can be carried out by the same method as theabove-described Method C.

The reaction is carried out by using 0.5. to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XII) with respect to Compound (II).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (II) orCompound (XII), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method I′

A compound in which Y′ is a bond with respect to Formula (X) is preparedby reacting Compound (II) or a salt thereof with Compound (XIII) or asalt thereof.

The present method can be carried out by the same method as theabove-described Method D.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XIII) with respect to Compound (II).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (II) orCompound (XIII), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method H″

A compound in which Y′ is —(C═O)— with respect to Formula (X′):

is prepared by reacting Compound (XIX″) represented by Formula (XIX″):

wherein the symbols have the meanings as defined above, or a saltthereof with Compound (XII) or a salt thereof.

The present method can be carried out by the same method as theabove-described Method C.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XII) with respect to Compound (XIX″).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XIX″) orCompound (XII), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method I″

A compound in which Y′ is a bond with respect to Formula (X′) isprepared by reacting Compound (XIX″) or a salt thereof with Compound(XIII) or a salt thereof.

The present method can be carried out by the same method as theabove-described Method D.

The reaction is carried out by using 0.5 to 5 equivalents, preferably0.8 to 2 equivalents, of Compound (XIII) with respect to Compound(XIX″).

The reaction temperature is −50 to 150° C., preferably −20 to 100° C.

The reaction time may vary depending on the type of Compound (XIX″) orCompound (XIII), types of solvent and base, reaction temperature or thelike, but is usually about 1 minute to about 100 hours, preferably about15 minutes to about 48 hours.

Method U′

Compound (X) or a salt thereof can be prepared by reacting Compound (X′)or a salt thereof with Compound (VIII).

The reaction conditions, reaction solvent, reaction time and the likefor the present reaction are set according to the reaction conditionsand the like described for the reaction between Compound (VII) andCompound (VIII) according to Method F, or a method equivalent thereto.

Other starting material Compounds (IV), (IV′), (VI), (VIII) and (IX) canbe prepared according to methods known per se, or methods equivalentthereto.

When the compounds are obtained in their free forms by theabove-described reactions, the compounds may be converted to salt formsaccording to conventional methods, and when the compounds are obtainedin salt forms, the compounds may be converted to free products or othersalts according to conventional methods.

Here, the salt may be any salt as long as it does not adversely affectthe reaction, but for example, the same ones as the salts used asCompound (I) may be mentioned.

In the respective reactions for the syntheses of the above-describedCompound (I) and starting material compounds, when a starting materialcompound has an amino group, a carboxyl group, a hydroxyl group or thelike as the substituent, those in which the protective groups that arein general likely to be used in peptide chemistry or the like have beenintroduced, may be used as such groups, and after the reaction, thedesired compounds can be obtained by eliminating the protective groups,if necessary.

For the protective group for amino group, for example, the same groupsas the above-described protective groups for imino group, and phthaloyland the like are used.

For the protective group for carboxyl group, for example, C₁₋₆ alkyl(for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,etc.) which may be substituted, allyl, benzyl, phenyl, trityl,trialkylsilyl and the like are used. For their substituent, halogen atom(for example, fluorine, chlorine, bromine, iodine, etc.), formyl, C₁₋₆alkylcarbonyl (for example, acetyl, propionyl, valeryl, etc.), nitro andthe like are used, and the number of substituents is about 1 to 3.

For the protective group for hydroxyl group, for example, C₁₋₆ alkyl(for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl,etc.) which may be substituted, C₇₋₁₀ aralkyl (for example, benzyl,etc.), formyl, C₁₋₆ alkylcarbonyl (for example, acetyl, propionyl,etc.), benzoyl, C₇₋₁₀ aralkylcarbonyl (for example, benzylcarbonyl,etc.), tetrahydropyranyl, furanyl, silyl and the like are used. Fortheir substituent, halogen atom (for example, fluorine, chlorine,bromine, iodine, etc.), C₁₋₆ alkyl (for example, methyl, ethyl,n-propyl, etc.), phenyl, C₇₋₁₀ aralkyl (for example, benzyl, etc.), C₁₋₆alkoxy (for example, methoxy, ethoxy, n-propoxy, etc.), nitro and thelike are used, and the number of substituents is about 1 to 4.

For the method of eliminating protective groups, methods known per se,or methods equivalent thereto are used, and for example, methods oftreating with acid, base, reduction, ultraviolet ray, hydrazine,phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammoniumfluoride, palladium acetate and the like are used.

The Compound (I) thus obtained can be isolated and purified from thereaction mixture by means that are known per se, for example, by usingmeans such as extraction, concentration, neutralization, filtration,recrystallization, column chromatography, thin layer chromatography andthe like.

The salt of the compound represented by Formula (I) can be prepared bymeans that are known per se, for example, by adding an inorganic acid oran organic acid to the compound represented by Formula (I).

When Compound (I) is obtained as optical isomers, these individualoptical isomers and mixtures thereof are of course included in the scopeof the invention, and if desired, these isomers can be opticallyresolved according to methods known per se, or can be preparedindividually.

Compound (I) may be also a hydrate, and hydrates and anhydrates are allincluded in the scope of the invention.

The compound represented by Formula (II′):

wherein P⁰ is a hydrogen atom or a protective group for imino group, andthe other symbols have the meanings as defined above, or a salt thereofis useful as a synthetic intermediate of pharmaceutical compound forCompound (I), or the like.

For the protective group for imino group represented by P⁰, the sameones as the above-described protective groups for imino grouprepresented by P¹, and the like are used.

The compound (I) or its salt of the present invention is safe with lowtoxicity (for example, it is superior as medicaments from the viewpointssuch as acute toxicity, chronic toxicity, genetic toxicity, reproductivetoxicity, cardiac toxicity, drug interactions, carcinogenicity, and thelike), inhibits FXa, and has anticoagulation effect; therefore it isuseful for preventing and treating various arterial and venousthrombosis of animals, in particular mammals (for example, human being,monkey, cat, pig, horse, cattle, mouse, rat, guinea pig, dog, rabbit,and the like), for example, myocardial infarction, cerebral infarction,deep vein thrombosis, pulmonary thromboembolism or atheroscleroticobliterans, economy-class syndrome, thromboembolism during and postoperation, and the following disorders.

Among these, it is preferably used for preventing and treating ischemiccerebral infarction (in particular, thromboembolic stroke due to atrialfibrillation, and the like; and ischemic cerebral infarction caused byprogression of atherosclerosis or activation of blood coagulationsystem), deep vein thrombosis or pulmonary thromboembolism.

Brain:

Prevention or treatment of cerebral infarction, ischemic cerebrovasculardisorder, thromboembolic stroke caused by atrial fibrillation, heartfailure or valvular disease, acute ischemic cerebral apoplexy, acutestage cerebral thrombosis, cerebrovascular contraction aftersubarachnoid hemorrhage, Alzheimer's disease, transient ischemic attack(TIA), mixed dementia, cerebrovascular dementia, asymptomatic/multiplecerebral infarction, lacunar infarction and the like, prognosisimprovement or secondary onset prevention of cerebral infarction,prevention or treatment of thrombus after an extracranial andintracranial arterial bypass operation, combination use or supplementaluse with a thrombolytic agent against cerebral infarction (among them,ischemic cerebrovascular disorder), combination therapy with ananti-platelet drug such as aspirin in preventing onset of cerebralinfarction. Heart:

Prevention or treatment of acute coronary disease such as acutemyocardial infarction, myocardial infarction, ischemic coronary disease,unstable angina, myocardiopathy, acute heart failure, congestive chronicheart failure, valvular disease and the like, prognosis improvement orsecondary onset prevention of acute coronary disease such as angina,prevention or treatment of thrombus formation after artificial valve orartificial heart replacement, prevention or treatment of vascularreocclusion and restenosis after coronary intervention such as stentindwelling or PTCA (percutaneous transluminal coronary angioplasty) oratherectomy, prevention or treatment of vascular reocclusion andrestenosis after coronary bypass operation, combination use orsupplemental use with a thrombolytic agent against acute coronarydisease, combination therapy with an anti-platelet drug such as aspirinin preventing onset of myocardial infarction. Periphery:

Prevention or treatment of deep vein thrombosis, chronic arterialobliterans, atherosclerotic obliterans, peripheral circulation failuresuch as Buerger's disease, peripheral circulation failure afterfrostbite, aneurysm, varix, adult respiratory distress syndrome, acuterenal failure, chronic renal disease (e.g. diabetic nephropathy, chronicglumerular nephritis, IgA nephropathy etc.), diabetic circulationdisorder, pain, nerve disorder, diabetic complication such as diabeticretinopathy and the like, prognosis improvement or secondary onsetprevention of deep vein thrombosis, prevention or treatment of deep veinthrombosis or pulmonary thromboembolism after a joint operationincluding total hip arthroplasty (THA) or total knee arthroplasty (TKA),prevention or treatment of deep vein thrombosis or pulmonarythromboembolism after an orthopedic, plastic surgical or generalsurgical operation including a spine operation, prevention or treatmentof thrombus after a peripheral vascular bypass operation or artificialvessel or vena cava filter indwelling, prevention or treatment ofreocclusion and restenosis after stent indwelling or PTA (percutaneoustransluminal angioplasty) or peripheral vascular intervention such asatherectomy, prevention or treatment of deep vein thrombosis orpulmonary thromboembolism accompanied with acute internal disease,combination use or supplemental therapy with a thrombolytic agentagainst deep vein thrombosis and pulmonary thromboembolism, combinationtherapy with an anti-platelet drug such as aspirin in therapy ofperipheral circulation failure such as arteriosclerotic obliterans.

Others:

Prevention or treatment of pulmonary embolism, acute pulmonary embolism,economy class syndrome, thrombocytopenia or activation of bloodcoagulation system or complement activation caused by dialysis,thrombocytopenia on a major operation, thrombocytopenic purpura,disseminated intravascular coagulation syndrome (DIC) developed in apatient suffering from progression of arteriosclerosis or cancermetastasis or systemic inflammatory reaction syndrome (SIRS) orpancreatitis or cancer or leukemia or a major operation or sepsis or thelike, various organ disorders such as liver function disorder caused byoligemia or ischemia or retention of blood, various organ failurescaused by progression of shock or DIC (e.g. lung failure, liver failure,kidney failure, heart failure etc.), systemic lupus erythematosus,diffuse collagen disease, hyperthyroidism, puerperal palsy and the like,inhibition of rejective response on transplantation, organ protection orfunction improvement on transplantation, prevention of perfusion bloodcoagulation during blood extracorporeal circulation, substitutetherapeutic use against development of thrombocytopenia caused byheparin administration, promotion of bedsore or wound healing,inhibition of activation of blood excessive coagulation reaction onvarious hormone supplement therapy, substitute therapeutic use for apatient resistant or contraindicative to a coumarin drug includingwarfarin, inhibition of activation of excessive coagulation reaction onadministration of a blood preparation or a blood coagulationfactor-containing preparation, and the like.

Compound (I) of the invention can be administered orally orparenterally, as received or as a mixture with a pharmaceuticallyacceptable carrier.

The preparation of the invention containing Compound (I) of theinvention may be exemplified, as a formulation for oral administration,by tablet (including sugar-coated tablet and film-coated tablet), pill,granule, powder, capsule (including soft capsule and microcapsule),syrup, emulsion, suspension or the like; and as a formulation forparenteral administration, by injectable preparation, infusion, dripinfusion, suppository or the like. It is also effective for thepreparation to be provided as combination sustained release preparationswith suitable bases (e.g., polymers of butyric acid, polymers ofglycolic acid, copolymers of butyric acid-glycolic acid, mixture ofpolymers of butyric acid and polymers of glycolic acid, polyglycerolfatty acid esters, etc.).

The content of Compound (I) in the preparation of the invention may varydepending on the form of preparation, but is usually 2 to 85% by weight,preferably 5 to 70% by weight, with respect to the total preparation.For the method of preparing Compound (I) in the above-describedformulations, it is possible to apply known preparation methods that aregenerally used in the related art. When the above-described formulationsare prepared, it is possible, if necessary, to prepare the formulationsby suitably adding appropriate amounts of excipient, binding agent,disintegrant, gliding agent, sweetener, surfactant, suspending agent,emulsifying agent and the like that are conventionally used in the artof pharmaceutical preparation.

For example, when Compound (I) is prepared into a tablet, preparationcan be carried out by adding excipient, binding agent, disintegrant,gliding agent and the like; while when prepared into a pill or agranule, preparation can be carried out by adding excipient, bindingagent, disintegrant and the like. When Compound (I) is prepared into apowder or a capsule, preparation can be carried out by adding excipientand the like; when prepared into a syrup, by adding sweetener and thelike; and while when prepared into an emulsion or a suspension, byadding suspending agent, surfactant, emulsifying agent and the like.

Examples of the excipient include lactose, white sugar, glucose, starch,sucrose, microcrystalline cellulose, powdered licorice, mannitol, sodiumhydrogen carbonate, calcium phosphate, calcium sulfate and the like.

Examples of the binding agent include a 5 to 10 wt % starch liquidpaste, a 10 to 20 wt % gum arabic solution or gelatin solution, a 1 to 5wt % tragacanth solution, a carboxymethylcellulose solution, a sodiumalginate solution, glycerin and the like.

Examples of the disintegrant include starch, calcium carbonate and thelike.

Examples of the gliding agent include magnesium stearate, stearic acid,calcium stearate, purified talc and the like.

Examples of the sweetener include glucose, fructose, invert sugar,sorbitol, xylitol, glycerin, simple syrup and the like.

Examples of the surfactant include sodium lauryl sulfate, Polysorbate80, sorbitan monofatty acid ester, Polyoxyl 40 stearate and the like.

Examples of the suspending agent include gum arabic, sodium alginate,carboxymethylcellulose sodium, methylcellulose, bentonite and the like.

Examples of the emulsifying agent include gum arabic, tragacanth,gelatin, Polysorbate 80 and the like.

In addition, when Compound (I) is prepared into the above-describedformulations, if desired, appropriate amounts of colorant, preservative,fragrance, flavoring agent, stabilizer, thickening agent and the likethat are conventionally used in the art of purification can be suitablyadded.

The preparation of the invention containing Compound (I) can be usedsafely with stability and low toxicity. Daily dose of the preparationmay vary depending on the condition or body weight of the patient, typeof compound, administration route and the like; however, for example,when the preparation is to be orally administered to a patient havingthrombosis, the daily dose for adult (body weight about 60 kg) is about1 to 1000 mg, preferably about 3 to 500 mg, and more preferably about 5to 300 mg, in terms of the effective ingredient (the compoundrepresented by Formula (I) or a salt thereof), which can be administeredall at once, or in 2 to 3 portions.

When Compound (I) of the invention is to be parenterally administered,it is usually administered in the form of liquid formulation (forexample, injectable preparation). Daily dose thereof may vary dependingon the subject of administration, subject organ, symptoms,administration method and the like; however, the preparation isfavorably administered, for example, in the form of injectablepreparation in an amount of usually about 0.01 mg to about 100 mg,preferably about 0.01 to about 50 mg, and more preferably about 0.01 toabout 20 mg, per 1 kg of body weight, through intravenous injection. Theinjectable preparation includes, in addition to intravenous injectablepreparation, subcutaneous injectable preparation, intradermal injectablepreparation, muscular injectable preparation, drip infusion preparationand the like, while the sustained preparation includes iontophoretictransdermal preparation and the like. Such injectable preparations areprepared by methods known per se, that is, by dissolving, suspending oremulsifying Compound (I) of the invention in sterile aqueous liquid oroily liquid. Examples of the aqueous liquid for injection includephysiological saline, isotonic solutions containing glucose or otherpharmaceutical adjuvants (for example, D-sorbitol, D-mannitol, sodiumchloride, etc.) and the like, and these may be used in combination withappropriate dissolution aids, for example, alcohol (for example,ethanol), polyalcohol (for example, propylene glycol, polyethyleneglycol), nonionic surfactant (for example, Polysorbate 80, HCO-50) andthe like. Examples of the oily liquid include sesame oil, soybean oiland the like, and these may be used in combination with dissolution aidssuch as benzyl benzoate, benzyl alcohol and the like. Furthermore,buffering agent (for example, phosphate buffer solution, sodium acetatebuffer solution), soothing agent (for example, benzalkonium chloride,procaine chloride, etc.), stabilizer (for example, human serum albumin,polyethylene glycol, etc.), preservative (for example, benzyl alcohol,phenol, etc.) and the like may be mixed therewith. Prepared injectionliquids are usually filled in ampoules.

The preparation of the invention can be used in combination withsuitable drugs (hereinafter, abbreviated to combination drugs) such asthrombolytic agent (e.g., TPA, heparin, urokinase, etc.), Alzheimer'sdrug (for example, Avan, Calan, etc.), anti-cholesterol drug (e.g.,HMG-CoA reductase inhibitor such as simvastatin or pravastatin, etc.),TG lower drug (e.g., Clofibrat, etc.), AII antagonistic drug (e.g.,candesartan cilexetil, losartan, etc.), antiplatelet drug (e.g.,clopidogrel, abciximab, aspirin, etc.), Ca antagonistic drug (e.g.,calslot, amlodipine, etc.), ACE inhibitor (e.g., enalapril, captopril,etc.), β-blocking drug (e.g., metoprolol, carvedilol, etc.),antiarrhythmic drug (e.g., procaine amide, etc.), and the like. Thesecombination drugs may be low molecular weight compounds, or may beproteins of high molecular weight, polypeptides, antibodies, vaccines orthe like. Here, the administration form of the compound of the inventionand the combination drugs is not particularly limited, and it isfavorable that the compound of the invention and the combination drugsare in a combined state upon administration. For such administrationform, for example, mention may be made of (1) administration of a singlepreparation obtained by simultaneously formulating the compound of theinvention and the combination drug, (2) simultaneous administrationthrough the same administration route of two preparations obtained byseparately formulating the compound of the invention and the combinationdrug, (3) administration with a time interval through the sameadministration route of two preparations obtained by separatelyformulating the compound of the invention and the combination drug, (4)simultaneous administration through different administration routes oftwo preparations obtained by separately formulating the compound of theinvention and the combination drug, (5) administration with a timeinterval through different administration routes of two preparationsobtained by separately formulating the compound of the invention and thecombination drug (for example, administration in order of the compoundof the invention A combination drug, or administration in the reverseorder), or the like. The amount of the combination drug to beadministered can be appropriately selected with reference to theclinically used dosage. The mixing ratio of the compound of theinvention and the combination drug can be appropriately selected inaccordance with the subject of administration, administration route,disease to be treated, symptoms, combination, and the like. For example,when the subject of administration is human, the combination drug may beused in an amount of 0.01 to 100 parts by weight relative to 1 part byweight of the compound of the invention.

Compound (I) of the invention has excellent FXa inhibiting effect, andis useful as an anti-coagulant capable of oral uptake and having lessside effect of hemorrhage. Compound (I) of the invention isadvantageously used for the prevention and/or treatment of variousdiseases caused by thrombus and infarction.

The present invention is further described in detail in reference toExamples, Preparation Examples and Experimental Examples, but they arenot intended to limit the invention and may be modified in the range notto be construed to limit the scope thereof.

The elution in column chromatography of Examples was carried out underobservation by means of TLC (Thin Layer Chromatography). In the TLCobservation, 60F254 (manufactured by Merck & Co., Inc.) or NH(manufactured by Fuji Silysia Chemical, Ltd.) were adopted as a TLCplate, the solvent used for the elution in column chromatography wasadopted as an eluent, a UV detector was adopted as the means fordetection. As the silica gel for column, Kieselgel 60 (70 to 230 meshes)or Kieselgel 60 (230 to 400 meshes) was used. As the basic silica gelfor column, NH-DM 1020 (manufactured by Fuji Silysia Chemical, Ltd.; 100to 200 mesh) was used. NMR spectra were measured with a Varian Gemini200 spectrometer by using tetramethylsilane as internal or externalstandard. The chemical shift was indicated by δ, and a coupling constantwas indicated by Hz. IR spectra were measured with a Shimadzu FTZR-8200spectrometer. The numeric value in parenthesis with regard to a mixedsolvent is a volumetric mixing ratio of each solvent. Moreover, “%” inthe solution represents the number of grams in 100 mL of a solution.Abbreviations employed in Examples are described below.

-   s: singlet-   d: doublet-   t: triplet-   q: quartet-   dd: double doublet-   m: multiplet-   br: broad-   brs: broad singlet-   brd: broad doublet-   J: coupling constant-   WSC: water soluble carbodiimide-   THF: tetrahydrofuran-   DMF: dimethylformamide-   DMSO: dimethyl sulfoxide-   HOBt: 1-hydroxybenzotriazole-   AIBN: 2,2′-azobis(isobutyronitrile)-   NBS: N-bromosuccinimide-   Me: methyl-   Et: ethyl-   Pr: propyl-   Bu: butyl-   Ac: acetyl

EXAMPLE 13-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazolehydrochloride

1a) tert-Butyl4-((5,6-dihydroimidazo[2,1-b][1,3]thiazol-3-yl)methyl)piperidine-1-carboxylatehydrobromide

tert-Butyl 4-(2-oxopropyl)piperidine-1-carboxylate (1.0 g) and5,5-dibromobarbituric acid (1.2 g) were dissolved in ether (30 mL) andmixed overnight. The precipitated crystals were filtered off, and thefiltrate was concentrated. To the residue were added ethylenethiourea(0.46 g) and ethanol (30 mL), and the mixture was refluxed overnight.The precipitated crystals were collected by filtration to give the titlecompound (0.55 g) as pale yellow crystals.

NMR (CDCl₃) δ: 1.02-1.21 (2H, m), 1.45 (9H, s), 1.66-1.91 (3H, m), 2.20(1H, d, J=6.9), 2.61-2.80 (2H, m), 3.73 (2H, t, J=9.3), 4.07-4.13 (2H,m), 4.22 (2H, t, J=9.3), 5.23 (1H, s).

1b)3-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-l-piperidinyl)methyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole

The compound (0.55 g) obtained in Example 1a) was dissolved intrifluoroacetic acid (10 mL) and mixed at room temperature for 1 hour.The solvent was concentrated, and then to the residue were addeddichloromethane (20 mL) and triethylamine (0.38 mL). With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (0.4 g), HOBt (0.23 g)and WSC (0.29 g) were added thereto and mixed at room temperature for 16hours. The reaction solution was basified with an aqueous potassiumcarbonate solution, then extracted with chloroform, and the extract wasdried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was purified with a basic silica gel column to give thetitle compound (0.13 g) as a white powder.

NMR (CDCl₃) δ: 1.08-1.22 (1H, m), 1.78-1.93 (3H, m), 2.25-2.31 (2H, m),2.53-2.69 (1H, m), 2.90-3.15 (4H, m), 3.59-3.85 (2H, m), 3.80-3.95 (3H,m), 4.32 (2H, t, J=9.2), 4.55-4.62 (1H, m), 5.40 (1H, s), 7.66 (1H, dd,J=2.2, 8.8), 7.95-8.05 (4H, m), 8.55 (1H, s).

1c)3-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)−5,6-dihydroimidazo[2,1-b][1,3]thiazolehydrochloride

The compound (0.23 g) obtained in Example 1b) was treated with asolution of hydrogen chloride in ether to give the title compound (0.16g) as white crystals.

NMR (DMSO-d₆) δ: 0.65-0.91 (1H, m), 0.96-1.22 (2H, m), 1.43-4.79 (3H,m), 2.30-2.47 (2H, m), 2.60-2.79 (2H, m), 2.84-3.12 (1H, m), 3.52-3.68(2H, m), 3.69-3.89 (1H, m), 4.07-4.40 (5H, m), 6.49 (1H, s), 7.96-7.73(1H, m), 7.93-7.97 (1H, m), 8.17-8.28 (3H, m), 8.61 (1H, s), 9.78 (1H,s).

EXAMPLE 23-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole

2a) tert-Butyl4-(5,6-dihydroimidazo[2,1-b][1,3]thiazol-3-yl)piperidine-1-carboxylatehydrobromide

tert-Butyl 4-acetylpiperidine-1-carboxylate (1.0 g) and5,5-dibromobarbituric acid (1.2 g) were dissolved in ether (30 mL) andmixed overnight. The precipitated crystals were filtered off, and thefiltrate was concentrated. To the residue were added ethylenethiourea(0.46 g) and ethanol (30 mL), and the mixture was refluxed overnight.The precipitated crystals were collected by filtration to give the titlecompound (0.55 g) as pale yellow crystals.

NMR (CDCl₃) δ: 1.12-1.58 (2H, m), 1.45 (9H, s), 1.68-2.05 (3H, m),2.60-2.88 (2H, m), 3.76 (2H, t, J=9.2), 4.05-4.15 (2H, m), 4.22 (2H, t,J=9.2), 5.23 (1H, s).

2b)3-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)−5,6-dihydroimidazo[2,1-b][1,3]thiazole

The compound (0.50 g) obtained in Example 2a) was dissolved intrifluoroacetic acid (10 mL) and mixed at room temperature for 1 hour.The solvent was distilled off, and to the residue were addeddichloromethane (20 mL) and triethylamine (0.38 mL). With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (0.4 g), HOBt (0.23 g)and WSC (0.29 g) were added thereto, and the mixture was mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified with a basic silica gelcolumn to give the title compound (0.16 g) as a white powder.

NMR (CDCl₃) δ: 1.21-1.61 (2H, m), 1.85-1.99 (2H, m), 2.33-2.50 (1H, m),2.55-2.62 (2H, m), 2.83-2.91 (2H, m), 3.01-3.13 (1H, m), 3.51-3.59 (1H,m), 3.77 (2H, t, J=9.2), 3.88-3.95 (1H, m), 4.22 (2H, t, J=9.2),4.55-4.62 (1H, m), 5.23 (1H, s), 7.58 (1H, dd, J=1.8, 8.8), 7.86-7.95(4H, m), 8.46 (1H, s).

EXAMPLE 33-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazolehydrochloride

3a) 1-(3-((6-Chloro-2-naphthyl)sulfonyl)propionyl)piperazine

tert-Butyl 1-piperazine carboxylate (5.0 g) was dissolved indichloromethane (20 mL), and triethylamine (3.8 mL) was added thereto.With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (8.0g), HOBt (4.5 g) and WSC (5.7 g) were added thereto, and the mixture wasmixed at room temperature for 16 hours. The reaction solution wasbasified with an aqueous potassium carbonate solution, then extractedwith chloroform, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was dissolved intrifluoroacetic acid (25 mL) and mixed at room temperature for 1 hour.After concentrating the reaction solution, the residue was basified withan aqueous potassium carbonate solution and extracted with chloroform.The extract was dried over anhydrous magnesium sulfate, and then thesolvent was concentrated to give the title compound (8.7 g) as a palebrown oily matter.

NMR (CDCl₃) δ: 2.77 (2H, t, J=5.1), 2.83-2.88 (4H, m), 3.42 (2H, t,J=9.2), 3.48-3.58 (4H, m), 7.57 (1H, dd, J=2.1, 9.0), 7.90-7.94 (4H, m),8.46 (1H, s).

3b)3-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole

The compound (1.0 g) obtained in Example 3a) was dissolved in DMF (30mL). Potassium carbonate (0.75 g) and3-chloromethyl−5,6-dihydroimidazo[2,1-b][1,3]thiazole hydrochloride(0.58 g) were added thereto, and the mixture was mixed at 70° C. for 4hours. After distilling off the solvent, the residue was poured intowater, extracted with a mixture of chloroform-methanol, and the extractwas dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the residue was purified with a basic silica gel column to givea colorless oily matter. The oily matter was dissolved in ethyl acetate,and a 4 N solution of hydrogen chloride in ethyl acetate (0.4 mL) wasadded thereto. The precipitated solid was collected by filtration togive the title compound (0.80 g) as a colorless powder.

NMR (DMSO-d₆) δ: 2.75-2.89 (4H, m), 3.46-3.67 (6H, m), 4.26-4.31 (6H,m), 4.56-4.68 (2H, m), 7.02-7.23 (1H, s), 7.73-7.79 (1H, m), 7.98-8.04(1H, m), 8.18-8.34 (3H, m), 8.67 (1H, s).

EXAMPLE 41-(3-((6-Chloro-2-naphthyl)sulfonyl)propyl)-4-(5,6-dihydroimidazo[2,1-b][1,3]thiazol-3-yl)methyl-2-piperazinonehydrochloride

4a) tert-Butyl4-(3-((6-chloro-2-naphthyl)thio)propyl)-3-oxopiperazine-1-carboxylate

tert-Butyl 3-oxopiperazine-1-carboxylate (2.0 g) was dissolved in DMF(30 mL), and sodium hydride (0.5 g) was added thereto. With ice cooling,2-chloro-6-((3-chloropropyl)thio)naphthalene (2.7 g) was added thereto,and the mixture was mixed at 60° C. for 3 hours. The reaction solutionwas poured into water, then extracted with chloroform, and the extractwas dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the residue was purified with a silica gel column to give thetitle compound (4.0 g) as a pale brown oily matter.

NMR (CDCl₃) δ: 1.48 (9H, s), 1.92-1.99 (2H, m), 3.05 (2H, t, J=6.8),3.34 (2H, t, J=5.8), 3.57 (2H, t, J=6.8), 3.64 (2H, t, J=5.8), 4.09 (2H,s), 7.40-7.46 (2H, m), 7.68-7.79 (4H, m).

4b) tert-Butyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propyl)-3-oxopiperazine-1-carboxylate

The compound (4.0 g) obtained in Example 4a) was dissolved in ethylacetate (50 mL). 3-Chloroperbenzoic acid (7.4 g) was added thereto at 5°C. or lower, and the mixture was mixed for 1 hour. The reaction solutionwas poured into an aqueous potassium carbonate solution, then extractedwith chloroform, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off to give the title compound (2.6g) as white crystals.

NMR (CDCl₃) δ: 1.48 (9H, s), 2.04-2.12 (2H, m), 3.18-3.23 (2H, m), 3.36(2H, t, J=8.0 ), 3.54 (2H, t, J=10.5), 3.66 (2H, t, J=8.0), 4.06 (2H,s), 7.61 (1H, dd, J=2.7, 13.8), 7.92-7.99 (4H, m), 8.48 (1H, s).

4c) 1-(3-((6-Chloro-2-naphthyl)sulfonyl)propyl)-2-piperazinone

The compound (2.6 g) obtained in Example 4b) was dissolved intrifluoroacetic acid (15 mL) and mixed at room temperature for 1 hour.The solvent was distilled off, and the residue was poured into anaqueous potassium carbonate solution. Then, the mixture solution wasextracted with chloroform, and the extract was dried over anhydrousmagnesium sulfate. The solvent was distilled off to give the titlecompound (2.4 g) as a brown oily matter.

NMR (CDCl₃) δ: 2.01-2.08 (2H, m), 3.07 (2H, t, J=4.6), 3.18-3.23 (2H,m), 3.31 (2H, t, J=4.6), 4.48-4.52 (4H, m), 7.58-7.60 (1H, m), 7.90-7.97(4H, m), 8.46 (1H, s).

4d)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propyl)-4-(5,6-dihydroimidazo[2,1-b][1,3]thiazol-3-yl)methyl-2-piperazinone

The compound (1.0 g) obtained in Example 4c) was dissolved in DMF (30mL). Potassium carbonate (0.75 g) and3-chloromethyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole hydrochloride(0.58 g) were added thereto, and the mixture was mixed at 70° C. for 4hours. After distilling off the solvent, the residue was poured intowater, extracted with a mixture of chloroform-methanol, and the extractwas dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the residue was purified with a basic silica gel column to givean oily matter. The oily matter was dissolved in acetone, a 4 N solutionof hydrogen chloride in diethyl ether was added thereto, and theprecipitated solid was collected by filtration to give the titlecompound (0.33 g) as a pale yellow powder.

NMR (DMSO-d₆) δ: 1.81-1.98 (2H, m), 3.42-3.98 (12H, m), 4.33-4.38 (2H,m), 4.51-4.55 (2H, m), 7.05 (1H, s), 7.82-7.87 (1H, m), 8.07-8.11 (1H,m), 8.26-8.42 (3H, m), 8.74 (1H, s), 9.84 (1H, brs)

Example 5N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminedihydrochloride

A suspension of 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine(2.5 g) obtained in Example 3a),N-((2Z)-4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (2.2 g) and potassium carbonate (2.4 g) in DMF (50 mL) wasmixed at 65° C. for 3 hours. The solvent was distilled off under reducedpressure, the residue was diluted with an aqueous potassium carbonatesolution, and extracted with chloroform. The extract was dried overanhydrous magnesium sulfate, and then concentrated under reducedpressure. The product, which was obtained by the purification of theresidue with a basic silica gel column, was dissolved in ethyl acetate.A solution of hydrogen chloride in ether was added thereto, and themixture was concentrated and dried to give the title compound (2.4 g) asa colorless powder.

NMR (CDCl₃) δ: 1.70-1.82 (2H, m), 2.44-2.55 (4H, m), 2.93-3.01 (2H, m),3.11 (3H, s), 3.34 (2H, s), 3.46 (3H, s), 3.53-3.70 (4H, m), 5.84 (1H,s), 7.68-7.73 (1H, m), 8.04-8.08 (4H, m), 8.58 (1H, s).

Example 6N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-propyl-1,3-thiazol-2(3H)-ylidene)-N-propylamine

In the same manner as in Example 3b), the title compound (1.5 g) as paleyellow crystals was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (2.0 g)obtained in Example 3a) andN-(4-chloromethyl-3-propyl-1,3-thiazol-2(3H)-ylidene)-N-propylaminehydrochloride (1.6 g).

NMR (CDCl₃) δ: 1.01-1.11 (6H, m), 1.72-1.83 (4H, m), 2.43-2.55 (4H, m),2.97 (2H, t, J=7.6), 3.14 (2H, t, J=7.0), 3.37 (2H, s), 3.53-3.70 (6H,m), 3.86 (2H, t, J=7.8), 5.76 (1H, s), 7.61 (1H, dd, J=1.4, 8.8),8.04-8.08 (4H, m), 8.58 (1H, s).

Example 7N-((2Z)-3-Butyl-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-1,3-thiazol-2(3H)-ylidene)-1-butylamine

In the same manner as in Example 3b), the title compound (1.7 g) as paleyellow crystals was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (2.5 g)obtained in Example 3a) andN-(3-butyl-4-chloromethyl-1,3-thiazol-2(3H)-ylidene)-N-butylaminehydrochloride (2.3 g).

NMR (CDCl₃) δ: 0.99-1.09 (6H, m), 1.37-1.76 (8H, m), 2.44-2.53 (4H, m),2.97 (2H, t, J=7.4), 3.17 (2H, t, J=7.0), 3.31 (2H, s), 3.53-3.70 (6H,m), 3.90 (2H, t, J=8.2), 5.76 (1H, s), 7.61 (1H, dd, J=1.4, 8.8),8.04-8.08 (4H, m), 8.59 (1H, s).

Example 8N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-ethyl-1,3-thiazol-2(3H)-ylidene)-N-ethylaminehydrochloride

The oily matter, which was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.5 g)obtained in Example 3a) andN-(4-chloromethyl-3-ethyl-1,3-thiazol-2(3H)-ylidene)-N-ethylaminehydrochloride (1.0 g) in the same manner as in Example 3b), wasdissolved in acetone (2 mL). A solution of hydrogen chloride in ethanolwas added thereto, and the precipitated solid was collected byfiltration to give the title compound (0.51 g) as white crystals.

NMR (DMSO-d₆) 8: 1.19 (3H, t, J=6.8), 1.29 (3H, t, J=7.3), 2.80 (3H, t,J=7.1), 3.39 (3H, dt, J=12.4, 6.2), 3.57-3.68 (3H, m), 3.95 (6H, s),4.33 (3H, s), 7.75 (1H, dd, J=8.7, 2.1), 8.00 (1H, dd, J=8.8, 1.8), 8.20(1H, d, J=8.9), 8.26-8.33 (2H, m), 8.66 (1, s).

Example 9N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-isopropyl-1,3-thiazol-2(3H)-ylidene)-N-isopropylaminehydrochloride

In the same manner as in Example 3b), the title compound (1.0 g) aswhite crystals was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.4 g)obtained in Example 3a) andN-(4-chloromethyl-3-isopropyl-1,3-thiazol-2(3H)-ylidene)-N-isopropylaminehydrochloride (1.0 g).

NMR (CDCl₃) δ: 1.23-1.27 (12H, m), 1.36-1.49 (2H, m), 2.45-2.54 (4H, m),2.93-2.96 (2H, m), 3.25 (2H, s), 3.55-3.70 (6H, m), 4.41-4.58 (1H, m),5.67 (1H, s), 7.68-7.73 (1H, m), 8.04-8.13 (4H, m), 8.58 (1H, s).

Example 10N-((2Z)-4-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride

10a) tert-Butyl4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperidine-1-carboxylatehydrobromide

tert-Butyl 4-(2-oxopropyl)piperidine-1-carboxylate (1.0 g) and5,5-dibromobarbituric acid (1.2 g) were dissolved in ether (30 mL) andmixed overnight. The precipitated crystals were filtered off, and thefiltrate was concentrated. To the residue were addedN,N′-dimethylthiourea (0.46 g) and ethanol (30 mL), and the mixture wasrefluxed overnight. The precipitated crystals were collected byfiltration to give the title compound (0.60 g) as a pale yellow oilymatter.

NMR (CDCl₃) δ: 1.01-1.15 (2H, m), 1.28 (9H, s), 1.62-1.72 (3H, m),2.31-2.34 (2H, m), 2.62-2.78 (3H, m), 2.98 (3H, s), 3.02 (2H, d, J=4.5),3.23 (3H, s), 5.52 (1H, s).

10b)N-((2Z)-4-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

The compound (1.2 g) obtained in Example 10a) was dissolved inconcentrated hydrochloric acid (5 mL) and mixed at room temperature for1 hour. The solvent was distilled off, and to the residue were addeddichloromethane (50 mL) and triethylamine (0.87 mL). With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (0.92 g), HOBt (0.52 g)and WSC (0.65 g) were added to the solution, and mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The reactionsolution was distilled off, and the residue was purified with a basicsilica gel column to give the title compound (0.31 g) as a colorlesspowder.

NMR (CDCl₃) δ: 0.94-1.16 (3H, m), 1.61-1.77 (3H, m), 2.26 (2H, d,J=6.6), 2.39-2.48 (1H, m), 2.77-2.84 (4H, m), 3.17 (3H, s), 3.47-3.61(2H, m), 3.75-3.80 (1H, m), 4.12-4.46 (1H, m), 5.46 (1H, s), 7.51 (1H,dd, J=1.8, 8.8), 7.83-7.90 (4H, m), 8.41 (1H, s).

Example 11N-((2Z)-4-((4-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

11a) tert-Butyl4-(((2Z)-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate

tert-Butyl piperazine-1-carboxylate (2.5 g) was dissolved inacetonitrile (50 mL). Potassium carbonate (3.7 g) andN-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (3.2 g) were added thereto, and the mixture was mixedunder reflux for 4 hours. The solvent was distilled off, and to theresidue was added an aqueous potassium bicarbonate solution. The mixturewas then extracted with chloroform, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified with a basic silica gel column to give the titlecompound (4.3 g) as a brown oily matter.

NMR (CDCl₃) δ: 1.43 (9H, s), 2.35-3.36 (3H, m), 2.97 (3H, s), 2.31 (2H,s), 3.33 (3H, s), 3.36-3.40 (4H, m), 5.69 (1H, s).

11b)N-((2Z)-4-((4-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

The compound (1.5 g) obtained in Example 11a) was dissolved inconcentrated hydrochloric acid (5 mL) and mixed at room temperature for1 hour. The reaction solution was concentrated, and then to the residuewere added dichloromethane (50 mL) and triethylamine (1.3 mL). With icecooling,(3-((1-tert-butoxycarbonyl-5-chloro-1H-indol-2-yl)sulfonyl)propionicacid (1.8 g), HOBt (0.77 g) and WSC (0.96 g) were added thereto, and themixture was mixed at room temperature for 16 hours. The reactionsolution was basified with an aqueous potassium carbonate solution, thenextracted with chloroform, and the extract was dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified with a basic silica gel column to give the title compound (0.31g) as white crystals.

NMR (CDCl₃) δ: 2.36-2.47 (4H, m), 2.93 (2H, t, J=7.6), 3.09 (3H, s),3.29 (2H, s), 3.43 (3H, s), 3.48-3.58 (4H, m), 3.76 (2H, t, J=7.6), 5.84(1H, s), 7.20 (1H, s), 7.33-7.49 (3H, m), 7.75 (1H, d, J=1.4).

Example 124-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-iminedihydrochloride

12a)4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-1,3-thiazol-2-amine

A suspension of 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine(1.5 g) obtained in Example 3a), 4-chloromethyl-1,3-thiazol-2-aminehydrochloride (0.76 g) and potassium carbonate (1.12 g) in acetonitrile(50 mL) was refluxed for 4 hours, and then the solvent was distilled offunder reduced pressure. The residue was diluted with potassiumcarbonate, and extracted with chloroform. The extract was dried overanhydrous magnesium sulfate, and then the solvent was distilled offunder reduced pressure. The residue was purified with a basic silica gelcolumn to give the title compound (1.4 g) as white crystals.

NMR (CDCl₃ ) δ: 2.37 (2H, t J=5.1), 2.44 (2H, t, J=5.1), 2.84 (2H, t,J=7.8), 3.38 (2H, s), 3.45-3.57 (6H, m), 4.92 (2H, brs), 6.31 (1H, s),7.58 (1H, dd, J=2.1, 9.0), 7.90-7.95 (4H, m), 8.45 (1H, s).

12b)4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-iminedihydrochloride

The compound (0.5 g) obtained in Example 11a) was dissolved in DMF (1.0mL), methyl iodide (0.13 mL) was added thereto at room temperature, andthe mixture was mixed at 80° C. overnight. The reaction solution waspoured into water and extracted with a mixed solution of chloroform andmethanol, and the extract was dried over anhydrous magnesium sulfate.The solvent was distilled off, and the residue was purified with a basicsilica gel column. The product was treated with a solution of hydrogenchloride in ether (5 mL) to give the title compound (0.23 g) as whitecrystals.

NMR (CDCl₃) δ: 2.28-2.41 (4H, m), 2.78-2.86 (2H, m), 3.15 (2H, s), 3.30(3H, s), 3.34-3.55 (6H, m), 5.57 (1H, s), 7.55 (1H, dd, J=1.8, 8.8),7.87-7.92 (4H, m), 8.43 (1H, s).

Example 13 Ethyl(2Z)-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-5-carboxylate

Ethyl(2Z)-3,4-dimethyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylate(2.8 g) was dissolved in 1,2-dichloroethane (30 mL). AIBN (0.1 g) andNBS (2.3 g) were added thereto, and the mixture was refluxed for 1 hour.The reaction solution was basified with an aqueous potassium carbonatesolution, and then extracted with chloroform. The extract was dried overanhydrous magnesium sulfate, and the solvent was distilled off. In thesame manner as in Example 3b), the title compound (0.14 g) as a whitepowder was obtained from the resulting ethyl(2Z)-4-bromomethyl-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylate(1.5 g) and 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine(1.5 g) obtained in Example 3a).

NMR (CDCl₃) δ: 1.28 (3H, t, J=7.2), 2.39-2.48 (4H, m), 2.79 (2H, t,J=7.8), 2.96 (3H, s), 3.37 (3H, s), 3.32-3.53 (6H, m), 3.81 (2H, s),4.19 (2H, q, J=7.2), 7.52 (1H, dd, J=1.8, 8.8), 7.86-7.91 (4H, m), 8.41(1H, s).

Example 14N-((2Z)-4-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

14a) tert-Butyl4-((2Z)-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)piperidine-1-carboxylatehydrobromide

tert-Butyl 4-acetylpiperidine-1-carboxylate (2.0 g) and5,5-dibromobarbituric acid (2.4 g) were dissolved in ether (30 mL) andmixed overnight. The precipitated crystals were filtered off, and thefiltrate was concentrated. To the residue were addedN,N′-dimethylthiourea (0.95 g) and ethanol (30 mL), and the mixture wasrefluxed overnight. The precipitated crystals were collected byfiltration to give the title compound (0.16 g) as pale yellow crystals.

NMR (CDCl₃) δ: 1.11-1.15 (2H, m), 1.45 (9H, s), 1.68-1.67 (3H, m),2.31-2.34 (2H, m), 2.62-2.68 (2H, m), 2.98 (3H, s), 3.02 (2H, d, J=4.5),3.23 (3H, s), 5.52 (1H, s).

14b)N-((2Z)-4-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

The compound (1.2 g) obtained in Example 14a) was dissolved in 1 Nhydrochloric acid and mixed for 1 hour. The reaction solution wasbasified with an aqueous potassium carbonate solution, then extractedwith chloroform, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and to the residue were addeddichloromethane (50 mL) and triethylamine (1.6 mL). With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (1.7 g), HOBt (0.97 g)and WSC (1.2 g) were added thereto, and the mixture was mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified with a basic silica gelcolumn to give the title compound (0.16 g) as a white powder.

NMR (CDCl₃) δ: 1.36-1.51 (2H, m), 1.94-2.11 (2H, m), 2.60-2.72 (2H, m),2.93-3.02 (2H, m), 3.04 (3H, s), 3.12-3.25 (1H, m), 3.33 (3H, s),3.61-3.69 (2H, m), 3.98-4.05 (1H, m), 4.66-4.72 (1H, m), 5.54 (1H, s),7.64 (1H, dd, J=1.8, 8.8), 8.00-8.04 (4H, m), 8.55 (1H, m).

Example 15N-((2Z)-5-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)carbonyl)-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

(2Z)-3,4-Dimethyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylicacid (0.6 g) was dissolved in dichloromethane (30 mL), and triethylamine(0.14 mL) was added thereto. With ice cooling,1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.0 g), HOBt(0.42 g) and WSC (0.57 g) were added thereto, and the mixture was mixedat room temperature for 16 hours. The reaction solution was basifiedwith an aqueous potassium carbonate solution, then extracted withchloroform, and the extract was dried over anhydrous magnesium sulfate.The solvent was distilled off, and the residue was purified with a basicsilica gel column to give the title compound (0.13 g) as a white powder.

NMR (CDCl₃) δ: 2.21-2.38 (2H, m), 2.24 (3H, s), 2.86-2.93. (2H, m), 2.99(3H, s), 3.27 (3H, s), 3.27-3.30 (2H, m), 3.50-3.64 (6H, m), 7.58 (1H,dd, J=1.8, 8.4), 7.91-7.97 (4H, m), 8.47 (1H, s).

Example 16N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-ethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

16a)4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-N-methyl-1,3-thiazol-2-amine

In the same manner as in Example 3b), the title compound (1.2 g) aswhite crystals was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.5 g)obtained in Example 3a) and 4-chloromethyl-N-methyl-1,3-thiazol-2-aminehydrochloride (0.81 g).

NMR (CDCl₃) δ: 2.37 (2H, t, J=5.1), 2.46 (2H, t, J=5.1), 2.82-2.87 (2H,m), 2.95 (3H, t, J=5.1), 3.40 (2H, s), 3.45-3.57 (6H, m), 5.15-5.16 (1H,m), 6.30 (1H, s), 7.58 (1H, dd, J=1.5, 8.7), 7.90-7.95 (4H, m), 8.45(1H, s).

16b)N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-ethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

The compound (0.5 g) obtained in Example 11a) was dissolved in DMF (1.0mL), ethyl iodide (0.21 mL) was added thereto at room temperature, andthe mixture was mixed at 80° C. overnight. The reaction solution waspoured into water, extracted with a mixed solution of chloroform andmethanol, and the extract was dried over anhydrous magnesium sulfate.The solvent was distilled off, and the residue was purified with a basicsilica gel column to give the title compound (0.04 g) as a colorlesspowder.

NMR (CDCl₃) δ: 1.22 (3H, t, J=6.9), 2.31-2.41 (4H, m), 2.81-2.86 (2H,m), 2.96 (3H, s), 3.20 (2H, s), 3.40-3.56 (6H, m), 3.85 (2H, q, J=6.9),5.68 (1H, s), 7.55 (1H, dd, J=1.8, 8.8), 7.86-7.93 (4H, m), 8.44 (1H,s).

Example 17 Methyl1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate

17a) 1-tert-Butyl 3-methyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine-1,3-dicarboxylate

1-tert-Butyl 3-methyl piperazine-1,3-dicarboxylate (JP-W No. 3-232864:5.0 g) was dissolved in dichloromethane (20 mL), and triethylamine (3.8mL) was added thereto. With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (8.0 g), HOBt (4.5 g)and WSC (5.7 g) were added thereto, and the mixture was mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off to give the title compound (8.7 g) as a pale brownoily matter.

NMR (CDCl₃) δ: 1.38 (9H, s), 2.85-3.01 (4H, m), 3.65 (3H, m), 3.50-3.61(4H, m), 3.97-4.15 (1.3H, m), 4.25-4.34 (0.7H, m), 4.48-4.70 (0.7H, m),4.92-4.96 (1.3H, m), 7.59 (1H, dd, J=2.1, 9.0), 7.90-7.94 (4H, m), 8.46(1H, s).

17b) Methyl1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate

The compound (2.4 g) obtained in Example 17a) was dissolved inconcentrated hydrochloric acid (15 mL) and mixed at room temperature for1 hour. The reaction solution was basified with an aqueous potassiumcarbonate solution, then extracted with chloroform, and the extract wasdried over anhydrous magnesium sulfate. The solvent was distilled off,and the residue was dissolved in DMF (30 mL). Potassium carbonate (0.84g) andN-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (0.65 g) were added thereto, and the mixture was mixed at70° C. for 4 hours. The solvent was distilled off, and the residue waspoured into water. The mixture was extracted with a mixed solution ofchloroform-methanol, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purifiedwith a basic silica gel column to give the title compound (0.98 g) as awhite powder.

NMR (CDCl₃) δ: 1.91-2.32 (2H, m), 2.64-3.10 (2H, m), 2.99 (3H, s),3.18-3.35 (1H, m), 3.24 (3H, s), 3.31-3.63 (5.6H, m), 3.65 (3H, s), 3.70(0.6H, s), 4.22-4.30 (0.4H, m), 4.32-4.48 (0.4H, m), 5.13 (1H, s), 5.74(1H, s), 7.57 (1H, dd, J=2.1, 8.0), 7.91-7.95 (4H, m), 8.46 (1H, s).

Example 183-(2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)ethyl)-1,3-thiazol-2(3H)-imine

18a) 3-((6-Chloro-2-naphthyl)sulfonyl)propionyl chloride

3-((6-Chloro-2-naphthyl)sulfonyl)propionic acid (14.9 g), thionylchloride (4.4 mL) and DMF (2 drops) were added to toluene (100 mL), andthe mixture was refluxed for 1.5 hours. The solvent was distilled offunder reduced pressure, and the residue was washed with ether and hexaneto give the title compound (15.5 g) as a brown solid.

NMR (CDCl₃) δ: 3.35-3.44 (2H, m), 3.49-3.57 (2H, m), 7.62 (1H, dd,J=2.0, 8.0), 7.87-8.00 (4H, m), 8.48 (1H, s).

18b)2-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)-1-piperidinyl)ethanol

To a solution of ice-cooled 2-(4-piperidyl)ethanol (3.70 g) and sodiumhydrogen carbonate (2.03 g) in water (50 mL)-THF (50 mL) was portionwiseadded the compound (7.57 g) obtained in Example 18a). The reactionmixture was mixed at 0° C. for 1 hour, and then THF was distilled offunder reduced pressure and extracted with ethyl acetate. The extract waswashed with water, and then dried over anhydrous magnesium sulfate. Thesolvent was distilled off, and the residue was purified with a silicagel column to give the title compound (6.18 g) as a brown oily matter.

NMR (CDCl₃) δ: 1.01-1.13 (2H, m), 1.45-1.56 (2H, m), 1.67-1.81 (2H, m),2.45-2.57 (1H, m), 2.80-2.90 (2H, m), 2.93-3.06 (1H, m), 3.52-3.60 (2H,m), 3.66-3.83 (3H, m), 4.44-4.50 (1H, m), 7.59 (1H, dd, J=1.8, 8.8),7.93-7.97 (4H, m), 8.47 (1H, s).

18c)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-4-(2-iodoethyl)piperidine

To a solution of the compound (6.18 g) obtained in Example 18b) in ethylacetate (100 mL), methane sulfonyl chloride (1.4 mL) was added with icecooling, and the mixture was mixed at 0° C. for 1.5 hours. The reactionsolution was washed with water and dried over anhydrous magnesiumsulfate, and the solvent was distilled off. The residue was dissolved inacetonitrile (100 mL), sodium iodide (11.3 g) was added thereto, and themixture was mixed at room temperature for 24 hours. The solvent wasdistilled off under reduced pressure, water was added thereto, and themixture was extracted with ethyl acetate. The extract was washed withwater, and then dried over anhydrous magnesium sulfate. The solvent wasdistilled off, and then the residue was purified with a silica gelcolumn to give the title compound (5.58 g).

NMR (CDCl₃) δ: 0.90-1.23 (2H, m), 1.60-1.84 (5H, m), 2.46-2.58 (1H, m),2.82-2.90 (2H, m), 2.95-3.08 (1H, m), 3.20 (2H, t, J=6.7), 3.51-3.60(2H, m), 3.79 -3.86 (1H, m), 4.46-4.53 (1H, m), 7.60 (1H, dd, J=1.8,8.8), 7.92-7.97 (4H, m), 8.48 (1H, s).

18d)3-(2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)ethyl)-1,3-thiazol-2(3H)-imine

1,3-Thiazol-2-amine (0.12 g) was dissolved in DMF (0.5 mL), and thecompound (0.6 g) obtained in Example 18c) was added thereto at roomtemperature, and the mixture was mixed at 80° C. overnight. The reactionsolution was poured into water, extracted with a mixed solution ofchloroform and methanol, and the extract was dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified with a basic silica gel column to give the title compound (0.11g) as a white powder.

NMR (CDCl₃) δ: 0.82-1.13 (2H, m), 1.38-1.84 (6H, m), 2.36-2.48 (1H, m),2.74-2.98 (3H, m), 3.45-3.54 (2H, m), 3.61-3.76 (3H, m), 4.35-4.42 (1H,m), 5.68 (1H, d, J=5.2), 6.29 (1H, d, J=5.2), 7.52 (1H, dd, J=1.8, 8.8),7.86-7.90 (4H, m), 8.40 (1H, s).

Example 194-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-2-piperazinone

tert-Butyl 3-oxopiperazine-1-carboxylate (1.5 g) was dissolved in DMF(50 mL), and sodium hydride (0.3 g) was added thereto. With ice cooling,N-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (1.6 g) was added thereto, and the mixture was mixed at80° C. for 3 hours. The solvent was distilled off, and the residue waspoured into water, then extracted with chloroform, and the extract wasdried over anhydrous magnesium sulfate. The solvent was distilled off togive1-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-2-piperazinone(1.7 g) as a pale brown oily matter (a crude product). The resultingoily matter was dissolved in concentrated hydrochloric acid (5 mL) andmixed at room temperature for 1 hour. After concentrating the reactionsolution, the residue was dissolved in dichloromethane (30 mL), andtriethylamine (1.4 mL) was added thereto. With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (1.5 g), HOBt (0.84 g)and WSC (1.0 g) were added thereto, and the mixture was mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified with a basic silica gelcolumn to give the title compound (0.25 g) as a colorless powder.

NMR (CDCl₃) δ: 2.51-2.84 (2H, m), 2.90 (3H, s), 3.12 (3H, s), 3.16-3.26(2H, m), 3.46-3.50 (2H, m), 3.52-3.74 (2H, m), 4.12-4.15 (2H, m),4.34-4.39 (2H, m), 5.76 (1H, s), 7.51 (1H, dd, J=2.2, 8.8), 7.83-7.91(4H, m), 8.40 (1H, s).

Example 20 Methyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate

1-tert-Butyl 3-methyl piperazine-1,3-dicarboxylate (1.5 g) was dissolvedin DMF (50 mL). Potassium carbonate (1.7 g) andN-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (1.4 g) were added thereto, and the mixture was mixed at80° C. overnight. The solvent was distilled off, the residue was pouredinto water, extracted with a mixed solution of chloroform-methanol, andthe extract was dried over anhydrous magnesium sulfate. The solvent wasdistilled off to give tert-butyl4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-3-oxopiperazine-1-carboxylate(1.2 g) as a pale brown oily matter. The resulting oily matter wasdissolved in trifluoroacetic acid (10 mL) and mixed at room temperaturefor 1 hour. The mixture was dissolved in dichloromethane (50 mL), andtriethylamine (0.87 mL) was added thereto. With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (0.97 g), HOBt (0.53 g)and WSC (0.65 g) were added thereto, and the mixture was mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off, and the residue was purified with a basic silica gelcolumn to give the title compound (1.8 g) as a white powder.

NMR (CDCl₃) δ: 2.38-2.52 (1H, m), 2.83-2.91 (3.7H, m), 2.94 (3H, s),3.23-3.40 (3.7H, m), 3.29 (3H, s), 3.48-3.66 (6.3H, m), 4.06-4.29 (1H,m), 4.77-4.96 (0.3H, m), 5.71 (0.3H, s), 7.73 (0.7H, s), 7.49-7.55 (1H,m), 7.88-7.94 (4H, m), 8.43 (1H, m).

Example 21(2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-N,3-dimethyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-5-carboxamide

In the same manner as in Example 13, the title compound (0.54 g) as awhite powder was obtained from(2Z)-N,3,4-trimethyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-5-carboxamide(2.0 g).

NMR (CDCl₃) δ: 2.39-2.51 (4H, m), 2.72-2.87 (5H, m), 2.94 (3H, s), 3.32(3H, s), 3.40-3.53 (6H, m), 5.24 (2H, s), 6.44-6.69 (1H, m), 7.52 (1H,dd, J=2.2, 8.8), 7.80-7.91 (4H, m), 8.40 (1H, s).

Example 22(2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-N,N,3-trimethyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-5-carboxamide

In the same manner as in Example 13, the title compound (0.27 g) as awhite powder was obtained from(2Z)-N,N,3,4-tetramethyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-5-carboxamide(2.0 g).

NMR (CDCl₃) δ: 2.31-2.42 (4H, m), 2.70-2.78 (2H, m), 2.93 (3H, s), 2.97(6H, s), 3.32 (3H, s), 3.35-3.51 (8H, m), 7.52 (1H, dd, J=2.2, 8.8),7.84-7.90 (4H, m), 8.39 (1H, s).

Example 23 tert-Butyl1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate

23a) Di-tert-butyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)piperazine-1,3-dicarboxylate

Di-tert-butyl piperazine-1,3-dicarboxylate (Wu, Guosheng, et al.,Enantiomer 6, pp. 343-345, (2001): 4.1 g) was dissolved indichloromethane (50 mL), and triethylamine (4.0 mL) was added thereto.With ice cooling, 3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (4.3g), HOBt (2.4 g) and WSC (3.0 g) were added thereto, and the mixture wasmixed at room temperature for 16 hours. The reaction solution wasbasified with an aqueous potassium carbonate solution, then extractedwith chloroform, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purifiedwith a silica gel column to give the title compound (5.0 g).

NMR (CDCl₃) δ: 1.43 (9H, s), 1.46 (9H, s), 2.84-3.11 (4H, m), 3.51-3.61(4H, m), 3.92-4.17 (1.3H, m), 4.25-4.35 (0.7H, m), 4.47-4.72 (0.7H, m),4.93-4.96 (0.7H, m), 7.58 (1H, dd, J=2.1, 9.0), 7.93-7.97 (4H, m), 8.48(1H, s).

23b) tert-Butyl1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate

The compound (5.0 g) obtained in Example 23a) was dissolved indichloromethane (50 mL). With ice cooling, tetramethylsilyl triflate(1.9 g) was added thereto, and the mixture was mixed for 30 minutes. Thereaction solution was basified with an aqueous potassium carbonatesolution, then extracted with chloroform, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was dissolved in DMF (50 mL). Potassium carbonate (2.4 g) andN-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (1.9 g) were added thereto, and the mixture was mixed at80° C. overnight. After distilling off the solvent, the residue waspoured into water, extracted with chloroform, and the extract was driedover anhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified with a silica gel column to give the title compound(4.2 g) as a white powder.

NMR (CDCl₃) δ: 1.34 (9H, s), 2.04-2.17 (2H, m), 2.79-2.88 (3H, m), 2.98(3H, s), 3.23 (2H, s), 3.27 (3H, s), 3.38-3.64 (4.2H, m), 4.20-4.32(0.8H, m), 4.95 (1H, s), 5.74 (1H, s), 7.58 (1H, dd, J=2.2, 8.0),7.87-8.00 (4H, m), 8.45 (1H, s).

Example 241-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylicacid dihydrochloride

tert-Butyl1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate(4.1 g) obtained in Example 23b) was dissolved in concentratedhydrochloric acid (15 mL) and mixed at room temperature for 1 hour. Thereaction solution was concentrated, and then water was removed from theresidue by azeotropy with toluene (30 mL), to give the title compound(4.2 g) as a white powder.

NMR (CDCl₃) δ: 2.03-2.42 (2H, m), 2.57-2.78 (2H, m), 2.80-2.97 (2H, m),3.00 (3H, s), 3.11-3.43 (2H, m), 3.61 (3H, s), 3.63-3.86 (2H, m),3.95-4.09 (1H, m), 4.86 (2H, s), 7.11 (1H, s), 7.74 (1H, dd, J=1.8,8.6), 7.96-8.03 (1H, m), 8.15-8.31 (3H, m), 8.64-8.66 (1H, m).

Example 251-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-(2-hydroxyethyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxamide

1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylicacid dihydrochloride (0.4 g) obtained in Example 24 was dissolved in DMF(20 mL), and triethylamine (0.2 mL) was added thereto. With ice cooling,2-ethanolamine (0.04 g), HOBt (0.12 g) and WSC (0.16 g) were addedthereto, and the mixture was mixed at room temperature for 16 hours. Thereaction solution was basified with an aqueous potassium carbonatesolution, then extracted with chloroform, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified with a basic silica gel column to give the titlecompound (0.21 g) as a white powder.

NMR (CDCl₃) δ: 1.82-2.20 (2H, m), 2.77-2.86 (2H, m), 2.95 (3H, s),3.05-3.45 (4H, m), 3.29 (3H, s), 3.49-3.80 (4.8H, m), 4.42-4.44 (0.6H,m), 5.12-5.15 (0.6H, m), 5.52-5.55 (2H, m), 5.78 (1H, s), 7.05-7.08(0.6H, m), 7.29-7.32 (0.4H, m), 7.59 (1H, dd, J=1.8, 8.7), 7.86-7.98(4H, m), 8.47 (1H, s).

Example 26N-(2-Amino-2-oxoethyl)-1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxamide

In the same manner as in Example 25, the title compound (0.19 g) aswhite crystals was obtained from aminoacetylamide (0.08 g).

NMR (CDCl₃) δ: 1.26-1.28 (2H, m), 2.04-2.22 (2H, m), 2.70-2.99 (2H, m),2.94 (3H, s), 3.10-3.26 (2H, m), 3.27 (3H, s), 3.36-3.93 (6.6H, m),4.01-4.18 (0.4H, m), 4.42 (0.4H, br), 5.14 (0.6H, br), 5.75 (1H, s),6.00-6.08 (0.4H, m), 6.18-6.30 (0.6H, m), 7.57-7.60 (1H, m), 7.88-7.98(4H, m), 8.46 (1H, s).

Example 27N-(2-(Acetylamino)ethyl)-1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxamide

In the same manner as in Example 25, the title compound (0.15 g) aswhite crystals was obtained from N-acetylethylenediamine (0.08 g).

NMR (CDCl₃) δ: 1.84 (3H, s), 1.93-2.20 (2H, m), 2.78-2.93 (2H, m), 2.95(3H, s), 3.10-3.33 (7H, m), 3.25 (3H, s), 3.59-3.70 (3.4H, m), 4.38(0.4H, br), 5.04 (0.6H, br), 5.45-5.68 (1.6H, m), 5.78 (1H, s), 7.22(1H, br), 7.53 (1H, br), 7.57 (1H, dd, J=1.8, 8.7), 7.91-7.98 (4H, m),8.48 (1H, s).

Example 281-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-methyl-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxamide

In the same manner as in Example 25, the title compound (0.23 g) aswhite crystals was obtained from methylamine hydrochloride (0.05 g).

NMR (CDCl₃) δ: 1.96-2.22 (2H, m), 2.71-2.89 (5H, m), 2.99 (3H, s),3.11-3.28 (3H, m), 3.31 (3H, s), 3.37-3.85 (4.4H, m), 4.02-4.13 (0.4H,m), 4.36-4.53 (0.6H, m), 5.15 (0.6H, s), 5.78 (1H, s), 6.41 (0.6H, br),6.71 (0.4H, br), 7.58-7.61 (1H, m), 7.87-7.97 (4H, m), 8.45 (1H, s).

Example 29N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-3-(4-morpholinylcarbonyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 25, the title compound (0.09 g) aswhite crystals was obtained from morpholine (0.07 g).

NMR (CDCl₃) δ: 217-2.45 (2H, m), 2.62-3.19 (4H, m), 3.06 (3H, s), 3.33(3H, s), 3.34-3.74 (12.2H, m), 4.00-4.22 (1.4H, m), 4.72-4.79 (0.4H, m),5.23-5.24 (1H, m), 5.84 (1H, s), 7.66 (1H, dd, J=1.8, 8.8), 7.98-8.05(4H, m), 8.54 (1H, s).

Example 30 tert-Butyl((2Z)-5-bromo-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)carbamate

30a) tert-Butyl 3,4-dimethyl-1,3-thiazol-2(3H)-ylidenecarbamate

4-Methyl-1,3-thiazol-2-amine (10 g) was dissolved in DMF (20 mL), methyliodide (6.5 mL) was added thereto at room temperature, and the mixturewas mixed at 80° C. for 2 hours. The reaction solution was concentrated,and the resulting yellow crystals were dissolved in dichloromethane (100mL). To the solution was added triethylamine (12 mL), was addeddi-tert-butyl dicarbonate (20 mL) at room temperature, and then themixture was mixed at room temperature for 16 hours. The reactionsolution was poured into water, extracted with chloroform, and theextract was dried over anhydrous magnesium sulfate. The solvent wasdistilled off to give the title compound (8.0 g) as white crystals.

NMR (CDCl₃) δ: 1.67 (9H, s), 2.36 (3H, d, J=1.4), 3.70 (3H, s), 6.29(1H, d, J=1.4).

30b) tert-Butyl(5-bromo-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)carbamate

The compound (3.0 g) obtained in Example 30a) was dissolved in carbontetrachloride (50 mL). AIBN (0.1 g) and NBS (2.3 g) were added theretoat room temperature, and the mixture was mixed at 80° C. for 1 hour. Thereaction solution was poured into an aqueous potassium carbonatesolution. The mixture was extracted with chloroform, and the extract wasdried over anhydrous magnesium sulfate. The solvent was distilled off togive the title compound (2.9 g) as white crystals.

NMR (CDCl₃) δ: 1.55 (9H, s), 2.26 (3H, s), 3.62 (3H, s).

30c) tert-Butyl((2Z)-5-bromo-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)carbamate

tert-Butyl (5-bromo-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)carbamate(2.9 g) obtained in Example 30b) was dissolved in 1,2-dichloroethane (50mL). AIBN (0.1 g) and NBS (1.7 g) were added thereto at roomtemperature, and the mixture was mixed at 80° C. for 3 hours. Thereaction solution was poured into an aqueous potassium carbonatesolution. The mixture was extracted with chloroform, and the extract wasdried over anhydrous magnesium sulfate. The solvent was distilled off togive tert-butyl(5-bromo-3-bromomethyl-4-methyl-1,3-thiazol-2(3H)-ylidene)carbamate (3.1g) as a brown oily matter. The resulting compound and1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.0 g)obtained in Example 3a) were dissolved in DMF (30 mL). Potassiumcarbonate (0.75 g) was added thereto and the mixture was mixed at 70° C.for 4 hours. The solvent was distilled off, and the residue was pouredinto water. The mixture was extracted with a mixed solution ofchloroform-methanol, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purifiedwith a basic silica gel column to give the title compound (1.2 g) as awhite powder.

NMR (CDCl₃) δ: 1.56 (9H, s) 2.38-2.49 (4H, m), 2.83-2.91 (2H, m),3.41-3.60 (8H, m), 3.73 (3H, s), 7.50 (1H, dd, J=2.2, 8.8), 7.92-7.97(4H, m), 8.47 (1H, s).

Example 315-Bromo-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-imine

tert-Butyl((2Z)-5-bromo-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)carbamate(1.2 g) obtained in Example 30c) was dissolved in trifluoroacetic acid(10 mL), and the mixture was mixed at room temperature for 1 hour. Thesolvent was distilled off, and the residue was poured into an aqueouspotassium carbonate solution. The mixture was extracted with a mixedsolution of chloroform-methanol, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified with a basic silica gel column to give the titlecompound (0.07 g) as a pale brown powder.

NMR (CDCl₃) δ: 2.39 (2H, t, J=5.1), 2.47 (2H, t, J=5.1), 2.86 (2H, t,J=7.8), 3.28 (2H, s), 3.36 (3H, s), 3.43-3.59 (6H, m), 7.58 (1H, dd,J=1.8, 8.4), 7.91-7.95 (4H, m), 8.46 (1H, s).

Example 32N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 3, the title compound (0.39 g) as awhite powder was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.0 g)obtained in Example 3a) andN-(4-chloromethyl-3,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (0.8 g).

NMR (CDCl₃) δ: 2.11 (3H, s), 2.35 (2H, t, J=5.4), 2.42 (2H, t, J=5.4),2.86 (2H, t, J=7.8), 3.00 (3H, s), 3.21 (2H, s), 3.36 (3H, s), 3.42-3.58(6H, m), 7.59 (1H, dd, J=1.8, 8.7), 7.88-7.95 (4H, m), 8.47 (1H, s).

Example 33 Ethyl(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazin-2-yl)acetate

33a) tert-Butyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-3-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate

tert-Butyl 3-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate (0.9 g) wasdissolved in dichloromethane (20 mL), and triethylamine (0.92 mL) wasadded thereto. With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (1.0 g), HOBt (0.55 g)and WSC (0.65 g) were added thereto, and the mixture was mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off to give the title compound (1.1 g) as a pale brownoily matter.

NMR (CDCl₃) δ: 1.15 (3H, t, J=7.2), 1.39 (9H, s), 2.42-2.98 (6H, m),3.18-3.34 (0.3H, m), 3.41-3.58 (2.7H, m), 3.92-4.13 (5H, m), 4.25-4.31(0.7H, m), 4.80-4.93 (0.3H, m), 7.48-7.56 (1H, m), 7.81-7.94 (4H, m),8.31-8.43 (1H, m).

33b) Ethyl(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-2-piperazinyl)acetate

The compound (1.1 g) obtained in Example 33a) was dissolved intrifluoroacetic acid (10 mL) and mixed at room temperature for 1 hour.The solvent was distilled off, and the residue was basified with anaqueous potassium carbonate solution. Then, the mixture was extractedwith chloroform, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was dissolved inDMF (20 mL). Potassium carbonate (0.55 g) andN-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (0.42 g) were added thereto and the mixture was mixed at70° C. for 4 hours. The solvent was distilled off, and then the residuewas poured into water. The mixture was extracted with a mixed solutionof chloroform-methanol, and the extract was dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified with a basic silica gel column to give the title compound (0.32g) as a white powder.

NMR (CDCl₃) δ: 1.18 (3H, t, J=7.2), 1.83-2.13 (3H, m), 2.41-2.48 (0.5H,m), 2.62-2.91 (5H, m), 2.99 (3H, s), 3.02-3.27 (3H, m), 3.34 (3H, s),3.47-3.62 (2H, m), 3.96-4.06 (2H, m), 4.34-4.38 (1H, m), 4.90-4.94(0.5H, m), 5.73 (1H, s), 7.55-7.60 (1H, m), 7.82-7.96 (4H, m), 8.46-8.48(1H, m)

Example 34N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-3-((3-(4-morpholinyl)-1,2,4-oxadiazol-5-yl)methyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

34a) 1-Aryl 4-tert-butyl2-(2-ethoxy-2-oxoethyl)piperazine-1,4-dicarboxylate

tert-Butyl 3-(2-ethoxy-2-oxoethyl)piperazine-1-carboxylate (5.5 g) was-dissolved in dichloromethane (50 mL), and triethylamine (6.3 mL) wasadded thereto. With ice cooling, aryl chloroformate (2.4 g) with icecooling was added thereto, and the mixture was mixed at room temperaturefor 1 hour. The reaction solution was basified with an aqueous potassiumcarbonate solution, then extracted with chloroform, and the extract wasdried over anhydrous magnesium sulfate. The solvent was distilled off togive the title compound (6.1 g) as a pale brown oily matter.

NMR (CDCl₃) δ: 1.25 (3H, t), 1.39 (9H, s), 2.63-3.10 (2H, m), 3.21-3.38(2H, m), 3.69 (3H, s), 3.81-4.10 (2H, m), 4.50-4.71 (4H, m), 5.16-5.31(2H, m), 5.77-6.02 (1H, m)

34b) 1-Aryl 4-tert-butyl2-((3-morpholin-4-yl)-1,2,4-oxadiazol-5-yl)piperazine-1,4-dicarboxylate

Morpholine-4-carboxamide oxime (2.1 g) was dissolved in anhydrous THF(50 mL), 4A molecular sieves powder (4.0 g) was added thereto, and themixture was mixed at room temperature 3 hours. Then, sodium hydride(0.57 g) was added thereto, and the mixture was mixed at 60° C. for 20minutes. To the reaction solution was added the compound (4.26 g)obtained in Example 34a), and refluxed for 1 hour. The reaction solutionwas concentrated, and the residue was purified with a silica gel columnto give the title compound (1.3 g) as a pale brown oily matter.

NMR (CDCl₃) δ: 1.38 (9H, s), 2.57 (4H, t, J=4.5), 2.81-3.03 (1H, m),3.24-3.47 (2H, m), 3.67 (2H, s), 3.72 (4H, t, J=4.5), 3.98-4.18 (2H, m),4.58-4.74 (3H, m), 5.19-5.40 (2H, m), 5.53-5.63 (1H, m), 5.80-5.99 (1H,m).

34c)N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-3-((3-(4-morpholinyl)-1,2,4-oxadiazol-5-yl)methyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

The compound (1.3 g) obtained in Example 34b) was dissolved in THF (20mL). 1,3-Dimethylbarbituric acid (1.9 g) andtetrakis(triphenylphosphine)palladium (0.3 g) were added thereto, andthe mixture was mixed at room temperature overnight having the reactorsubstituted with nitrogen. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off, the residue was dissolved in dichloromethane (20 mL),and triethylamine (0.92 mL) was added thereto. With ice cooling,3-((6-chloro-2-naphthyl)sulfonyl)propionic acid (1.0 g), HOBt (0.55 g)and WSC (0.65 g) were added thereto, and the mixture was mixed at roomtemperature for 16 hours. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off to give tert-butyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-3-((3-(4-morpholinyl)-1,2,4-oxadiazol-5-yl)methyl)piperazine-1-carboxylate(2.3 g) as a pale brown oily matter. The resulting oily matter wasdissolved in trifluoroacetic acid (15 mL), and mixed at room temperaturefor 1 hour. The reaction solution was concentrated, and then the residuewas basified with an aqueous potassium carbonate solution. The mixturewas then extracted with chloroform, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was dissolved in DMF (30 mL). Potassium carbonate (1.0 g) andN-(4-chloromethyl-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (0.77 g) were added thereto and the mixture was mixed at70° C. for 4 hours. The solvent was distilled off, and then the residuewas poured into water. The mixture was extracted with a mixed solutionof chloroform-methanol, and the extract was dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified with a basic silica gel column to give the title compound (0.19g) as a white powder.

NMR (CDCl₃) δ: 2.09-2.19 (1H, m), 2.39-2.61 (5H, m), 2.84-2.89 (1H, m),2.96 (3H, s), 3.01 (3H, s), 3.06-3.30 (3H, m), 3.49-3.61 (6H, m),3.64-3.78 (6H, m), 5.73 (1H, s), 5.86 (1H, s), 7.58 (1H, dd, J=2.4,9.0), 7.88-7.96 (4H, m), 8.48 (1H, s).

Example 35((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methanol

35a) tert-Butyl4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate

tert-Butyl4-(((2Z)-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate(1.0 g) obtained in Example 11a) was dissolved in THF (20 mL),n-butyllithium (4.6 mL; a 1.6 M hexane solution) was added thereto at−70° C., and the mixture was mixed for 30 minutes. To the reactionsolution was added DMF (1.0 mL), mixed at −70° C. for 1 hour, and thenan aqueous ammonium chloride solution was added thereto at 0° C. Themixture was extracted with ethyl acetate, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off to give thetitle compound (1.1 g) as a pale brown oily matter.

NMR (CDCl₃) δ: 1.46 (9H, s), 2.40-2.52 (4H, m), 3.06 (3H, s), 3.42-3.45(4H, m), 3.49 (3H, s), 3.67 (2H, s), 9.75 (1H, s).

35b) tert-Butyl4-(((2Z)-5-hydroxymethyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate

The compound (1.1 g) obtained in Example 35a) was dissolved in a mixedsolution of methanol (15 mL) and chloroform (15 mL). Sodium borohydride(0.18 g) was added thereto at 0° C., and the mixture was mixed at roomtemperature for 1 hour. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off to give the title compound (1.1 g) as pale browncrystals.

NMR (CDCl₃) δ: 1.45 (9H, s), 2.39-2.44 (4H, m), 2.99 (3H, s), 3.34 (3H,s), 3.34-3.43 (6H, m), 4.49 (2H, s).

35c)((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methanol

The compound (1.1 g) obtained in Example 35b) was dissolved inconcentrated hydrochloric acid (10 mL) and mixed at room temperature for1 hour. The reaction solution was concentrated, and then the residue wasdissolved in a mixed solution of a saturated aqueous sodium bicarbonatesolution (15 mL) and chloroform (15 mL).3-((6-Chloro-2-naphthyl)sulfonyl)propionyl chloride (1.1 g) was addedthereto at 0° C., and the mixture was mixed at room temperature for 2hours. The reaction solution was poured into water, extracted with amixed solution of chloroform-methanol, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified with a basic silica gel column to give the titlecompound (0.50 g) as a white powder.

NMR (CDCl₃) δ: 2.38 (2H, t, J=5.1), 2.46 (2H, t, J=5.1), 2.86 (2H, t,J=8.1), 2.99 (3H, s), 3.32 (2H, s), 3.33 (3H, s), 3.44 (2H, t, J=5.1),3.50-3.57 (4H, m), 4.48 (2H, s), 7.58 (1H, dd, J=2.1, 9.0), 7.90-7.96(4H, m), 8.45 (1H, s).

Example 36N-((2Z)-4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-5-((dimethylamino)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

36a) tert-Butyl4-(((2Z)-5-((dimethylamino)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate

tert-Butyl4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate(1.0 g) obtained in Example 35a) and a 1 M solution of dimethylamine inTHF (2.6 mL) were dissolved in a mixed solution of 1,2-dichloroethane(50 mL) and acetic acid (0.18 mL). Triacetoxy sodium borohydride (0.84g) was added thereto at 0° C., and the mixture was mixed at roomtemperature overnight. The reaction solution was basified with anaqueous potassium carbonate solution, then extracted with chloroform,and the extract was dried over anhydrous magnesium sulfate. The solventwas distilled off to give the title compound (1.1 g) as pale browncrystals.

NMR (CDCl₃) δ: 1.46 (9H, s), 2.25 (6H, s), 2.35-2.40 (4H, m), 3.01 (3H,s), 3.27 (2H, s), 3.36 (3H, s), 3.40-3.50 (4H, m), 3.74 (2H, s).

36b)N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-5-((dimethylamino)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

The compound (1.1 g) obtained in Example 36a) was dissolved inconcentrated hydrochloric acid (10 mL) and mixed at room temperature for1 hour. The reaction solution was concentrated, and then the residue wasdissolved in a mixed solution of a saturated aqueous sodium bicarbonatesolution (15 mL) and chloroform (15 mL). 3-((6-Chloro-2-naphthyl)sulfonyl)propionyl chloride (0.89 g) was added thereto at 0° C., and themixture was mixed at room temperature for 2 hours. The reaction solutionwas poured into water, then extracted with a mixed solution ofchloroform-methanol, and the extract was dried over anhydrous magnesiumsulfate. The solvent was distilled off, and the residue was purifiedwith a basic silica gel column to give the title compound (0.22 g) as awhite powder.

NMR (CDCl₃) δ: 2.25 (6H, s), 2.34-2.43 (4H, m), 2.83-2.91 (2H, m), 3.00(3H, d, J=1.8), 3.24-3.27 (2H, m), 3.28 (2H, s), 3.34 (3H, d, J=1.8),3.44-3.59 (6H, m), 7.60 (1H, dd, J=1.4, 8.8), 7.92-7.97 (4H, m), 8.47(1H, s).

Example 37N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-5-(4-morpholinylmethyl)-1,3-thiazol-2(3H)-ylidene)-N-methylamine

37a) tert-Butyl4-(((2Z)-3-methyl-2-(methylimino)-5-(4-morpholinyl)methyl-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate

tert-Butyl4-(((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-1-carboxylate(1.0 g) obtained in Example 35a) and morpholine (0.36 mL) were dissolvedin a mixed solution of 1,2-dichloroethane (50 mL) and acetic acid (0.18mL). Triacetoxy sodium borohydride (0.84 g) was added thereto at 0° C.,and the mixture was mixed at room temperature overnight. The reactionsolution was basified with an aqueous potassium carbonate solution, thenextracted with chloroform, and the extract was dried over anhydrousmagnesium sulfate. The solvent was distilled off to give the titlecompound (1.2 g) as pale brown crystals.

NMR (CDCl₃) δ: 1.46 (9H, s), 2.35-2.40 (4H, m), 2.43-2.47 (4H, m), 3.01(3H, s), 3.27 (2H, s), 3.35 (3H, s), 3.37-3.42 (4H, m), 3.69-3.71 (4H,m), 3.74 (2H, s).

37b)N-((2Z)-4-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-5-(4-morpholinylmethyl)-1,3-thiazol-2-(3H)-ylidene)-N-methylamine

The compound (1.2 g) obtained in Example 37a) was dissolved inconcentrated hydrochloric acid (10 mL) and mixed at room temperature for1 hour. The reaction solution was concentrated, and then the residue wasdissolved in a mixed solution of a saturated aqueous sodium bicarbonatesolution (15 mL) and chloroform (15 mL).3-((6-Chloro-2-naphthyl)sulfonyl)propionyl chloride (0.89 g) was addedthereto at 0° C., and the mixture was mixed at room temperature for 2hours. The reaction solution was poured into water, then extracted witha mixed solution of chloroform-methanol, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified with a basic silica gel column to give the titlecompound (0.22 g) as a white powder.

NMR (CDCl₃) δ: 2.18-2.44 (8H, m), 2.84-2.92 (2H, m), 3.01 (3H, s), 3.28(2H, s), 3.35 (3H, s), 3.35-3.40 (2H, m), 3.43-3.55 (6H, m), 3.68-3.73(4H, m), 7.60 (1H, dd, J=1.4, 8.8), 7.92-7.97 (4H, m), 8.48 (1H, s).

Example 38((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methanol

38a) tert-Butyl4-(((2E)-4-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)piperidine-1-carboxylate

In the same manner as in Example 35a), the title compound (2.7 g) wasobtained from tert-butyl4-(((2E)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)piperidine-1-carboxylate(2.2 g).

NMR (CDCl₃) δ: 1.48 (9H, s), 1.63-1.87 (4H, m), 2.70-2.86 (2H, m), 3.04(3H, s), 3.38-3.48 (1H, m), 3.56 (3H, s), 4.22-4.49 (2H, m), 9.77 (1H,s).

38b) tert-Butyl4-(((2E)-4-hydroxymethyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)piperidine-1-carboxylate

In the same manner as in Example 35b), the title compound (1.6 g) wasobtained from the compound (2.7 g) obtained in Example 38a).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.52-1.72 (4H, m), 2.68-2.82 (2H, m), 2.96(3H, s), 3.18-3.29 (1H, m), 3.33 (3H, s), 4.15-4.21 (2H, m), 4.43 (2H,s).

38c)((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methanol

In the same manner as in Example 35c), the title compound (0.06 g) as acolorless powder was obtained from the compound (1.6 g) obtained inExample 38b).

NMR (CDCl₃) δ: 1.47-1.84 (5H, m), 2.48-2.60 (1H, m), 2.85-3.25 (3H, m),2.93 (3H, s), 3.30 (3H, s), 3.52-3.60 (2H, m), 3.87-3.93 (1H, m), 4.41(2H, s), 4.53-4.60 (1H, m), 7.59 (1H, dd, J=2.0, 8.8), 7.88-7.98 (4H,m), 8.48 (1H, s).

Example 39N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-4-((dimethylamino)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

39a) tert-Butyl4-(((2E)-4-((dimethylamino)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)piperidine-1-carboxylate

In the same manner as in Example 36a), the title compound (1.1 g) a-sa-white powder was obtained from; tert-butyl4-(((2E)-4-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)piperidine-1-carboxylate(0.9 g) obtained in Example 38a) and a 1 M solution of dimethylamine inTHF (2.6 mL).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.53-1.95 (4H, m), 2.22 (6H, s), 2.69-2.89(3H, m), 2.98 (3H, s), 3.15 (2H, s), 3.33 (3H, s), 4.17-4.23 (2H, m).

39b)N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-4-((dimethylamino)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 36b), the title compound (0.43 g) as awhite powder was obtained from the compound (1.1 g) obtained in Example39a) and 3-((6-chloro-2-naphthyl)sulfonyl)propionyl chloride (0.89 g).

NMR (CDCl₃) δ: 1.47-1.70 (5H, m), 2.22 (6H, s), 2.49-2.61 (1H, m),2.86-2.94 (2H, m), 2.98 (3H, s), 3.01-3.09 (1H, m), 3.14 (2H, s), 3.34(3H, s), 3.53-3.61 (2H, m), 3.88-3.95 (1H, m), 4.58-4.64 (1H, m), 7.59(1H, dd, J=1.8, 8.8), 7.88-7.98 (4H, m), 8.48 (1H, s).

Example 40N-((2Z)-4-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-5-((dimethylamino)methyl)-3-methyl-1,3-thiazol-2(-3H)-ylidene)-N-methylamine

40a) tert-Butyl4-((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)piperidine-1-carboxylate

In the same manner as in Example 35a), the title compound (2.4 g) wasobtained from tert-butyl4-((2Z)-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazol-4-yl)piperidine-1-carboxylatehydrobromide (2.2 g) obtained in Example 14a).

NMR (CDCl₃) δ: 1.49 (9H, s), 1.90-2.00 (4H, m), 2.73-2.79 (2H, m), 3.05(3H, s), 3.14-3.25 (1H, m), 3.47 (3H, s), 4.31-4.37 (2H, m), 9.88 (1H,s).

40b) tert-Butyl4-((2Z)-5-((dimethylamino)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)piperidine-1-carboxylate

In the same manner as in Example 39a), the title compound (0.5 g) wasobtained from the compound (0.75 g) obtained in Example 40a) and a 1 Msolution of dimethylamine in THF (2.2 mL).

NMR (CDCl₃) δ: 1.49 (9H, s), 1.64-2.09 (4H, m), 2.26 (6H, s), 2.72-2.81(3H, m), 2.99 (3H, s), 3.31 (3H, s), 3.32 (2H, s), 4.22-4.28 (2H, m).

40c)N-((2Z)-4-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-5-((dimethylamino)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 36b), the title compound (0.11 g) as awhite powder was obtained from the compound (0.5 g) obtained in Example40b) and 3-((6-chloro-2-naphthyl)sulfonyl)propionyl chloride (0.43 g).

NMR (CDCl₃) δ: 1.76-1.94 (4H, m), 2.05-2.20 (1H, m), 2.24 (6H, s),2.50-2.59 (1H, m), 2.83-3.13 (3H, m), 2.98 (3H, s), 3.29 (2H, s), 3.30(3H, s), 3.48-3.60 (2H, m), 3.97-4.01 (1H, m), 4.69-4.73 (1H, m), 7.58(1H, dd, J=1.4, 8.8), 7.89-7.96 (4H, m), 8.47 (1H, s).

Example 41N-(((2Z)-4-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)-2-methoxy-N-methylethylamine

41a) tert-Butyl4-((2Z)-5-(((2-methoxyethyl)(methyl)amino)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)piperidine-1-carboxylate

In the same manner as in Example 39a), the title compound (0.5 g) wasobtained from tert-butyl4-((2Z)-5-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)piperidine-1-carboxylate(0.75 g) obtained in Example 40a) and 2-methoxy-N-methylethylamine (0.23g).

NMR (CDCl₃) δ: 1.48 (9H, s), 1.64-1.95 (4H, m), 2.30 (3H, s), 2.61 (2H,t, J=5.8), 2.71-2.82 (3H, m), 2.98 (3H, s), 3.31 (3H, s), 3.36 (3H, s),3.46 (2H, s), 3.52 (2H, t, J=5.8), 4.17-4.32 (2H, m).

41b)N-(((2Z)-4-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)-2-methoxy-N-methylethylamine

In the same manner as in Example 36b), the title compound (0.17 g) as awhite powder was obtained from the compound (0.5 g) obtained in Example41a) and 3-((6-chloro-2-naphthyl)sulfonyl)propionyl chloride (0.43 g).

NMR (CDCl₃) δ: 1.72-2.12 (5H, m), 2.28 (3H, s), 2.49-2.61 (3H, m),2.86-3.13 (3H, m), 2.98 (3H, s), 3.29 (3H, s), 3.34 (3H, s), 3.43 (2H,s), 3.48-3.59 (4H, m), 3.96-4.00 (1H, m), 4.68-4.73 (1H, m), 7.59 (1H,dd, J=1.4, 8.8), 7.89-7.96 (4H, m), 8.48 (1H, s).

Example 42(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3,4,5-tetrahydro-6H-pyrrolo[3,4-d][1,3]thiazol-6-one

42a) Benzyl4-((((2Z)-5-(ethoxycarbonyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)amino)piperidine-1-carboxylate

Ethyl(2Z)-4-bromomethyl-3-methyl-2-methylimino-2,3-dihydro-1,3-thiazole-5-carboxylate(3.0 g) obtained in Example 13) as a synthetic intermediate and benzyl4-aminopiperidine-1-carboxylate (3.3 g) were dissolved in DMF (50 mL).Potassium carbonate (3.8 g) was added thereto, and the mixture was mixedat 70° C. for 4 hours. The solvent was distilled off, and the residuewas poured into water. The mixture was then extracted with a mixedsolution of chloroform-methanol, and the extract was dried overanhydrous magnesium sulfate. The solvent-was distilled off, and theresidue was purified with a silica gel column to give the title compound(3.1 g) as pale yellow crystals.

NMR (CDCl₃) δ: 1.22-1.46 (2H, m), 1.33 (3H, t, J=7.4), 1.62-1.99 (3H,m), 2.61-2.82 (1H, m), 2.86-3.00 (1H, m), 3.01 (3H, s), 3.42 (3H, s),4.05 (2H, s), 4.05-4.14 (2H, m), 4.25 (2H, q, J=7.4), 5.12 (2H, s),7.34-7.37 (5H, m).

42b) Benzyl4-((2Z)-3-methyl-2-(methylimino)-6-oxo-2,3,4,6-tetrahydro-5H-pyrrolo[3,4-d][1,3]thiazol-5-yl)piperidine-1-carboxylate

The compound (3.1 g) obtained in Example 42a) and sodium hydroxide (0.59g) were dissolved in methanol (30 mL) water (10 mL) and mixed at 80° C.for 30 minutes. The reaction solution was acidified with 1 Nhydrochloric acid, and the solvent was distilled off. The residue wasdissolved in DMF (50 mL), and triethylamine (0.87 mL) was added thereto.With ice cooling, HOBt (1.0 g) and WSC (1.4 g) were added thereto, andthe mixture was mixed at room temperature for 16 hours. The reactionsolution was basified with an aqueous potassium carbonate solution, thenextracted with chloroform, and the extract was dried over anhydrousmagnesium sulfate. The solvent was distilled off, and the residue waspurified with a basic silica gel column to give the title compound (1.4g) as a brown oily matter.

NMR (CDCl₃) δ: 1.52-1.71 (2H, m), 1.79-1.85 (2H, m), 2.00-2.28 (1H, m),2.81-3.04 (2H, m), 3.03 (3H, s), 3.29 (3H, s), 4.07 (2H, s), 4.29-4.35(2H, m), 5.13 (2H, s), 7.36-7.38 (5H, m).

42c)(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3,4,5-tetrahydro-6H-pyrrolo[3,4-d][1,3]thiazol-6-one

The compound (1.4 g) obtained in Example 42b) was dissolved in asolution of hydrogen bromide in acetic acid (10 mL) and mixed at roomtemperature for 1 hour. The precipitated crystals were collected byfiltration, and then dissolved in a mixed solution of a saturatedaqueous sodium bicarbonate solution (15 mL) and chloroform (15 mL).3-((6-Chloro-2-naphthyl)sulfonyl)propionyl chloride (1.1 g) was addedthereto at 0° C., and the mixture was mixed at room temperature for 2hours. The reaction solution was poured into water, then extracted witha mixed solution of chloroform-methanol, and the extract was dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresidue was purified with a basic silica gel column to give the titlecompound (1.2 g) as white crystals.

NMR (CDCl₃) δ: 1.51-1.61 (2H, m), 1.81-2.05 (2H, m), 2.58-2.70 (1H, m),2.84-2.98 (2H, m), 3.03 (3H, s), 3.12-3.18 (1H, m), 3.28 (3H, s),3.50-3.67 (2H, m), 3.93-3.99 (1H, m), 4.07 (2H, s), 4.14-4.41 (1H, m),4.66-4.74 (H, m), 7.61 (1H, dd, J=1.4, 8.8), 7.89-7.98 (4H, m), 8.49(1H, s).

Example 431-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxamide

43a) Di-tert-butyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)piperazine-1,3-dicarboxylate

3-((6-Chloro-2-naphthyl)sulfonyl)propanoic acid (0.33 g), HOBt (2.30 g)and WSC (2.88 g) were added to acetonitrile (50 mL) and mixed for 15minutes. Then, di-tert-butyl piperazine-1,3-dicarboxylate (2.99 g) andtriethylamine (3.03 g) were added thereto, and the mixture was mixed atroom temperature for 15 hours. The reaction solution was concentratedunder reduced pressure, and the residue was diluted with ethyl acetateand an aqueous potassium carbonate solution. The organic layer wascollected by separation, and dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the residue was purified with a silicagel column to give the title compound (2.40 g) as a colorless powder.

NMR (CDCl₃) δ: 1.42-1.47 (18H, m), 2.80-4.94 (11H, m), 7.60 (1H, dd,J=2.0, 8.8), 7.89-7.97 (4H, m), 8.47 (1H, s).

43b) tert-Butyl 1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)piperazine-2-carboxylate

The compound (0.57 g) obtained in Example 43a) was dissolved indichloromethane (10 mL). While cooling the mixture to 0° C.,trimethylsilyl trifluoromethanesulfonate (0.27 g) was added thereto, andthe mixture was mixed at 0° C. for 1 hour. To the reaction solution wasbasified by adding a saturated aqueous sodium bicarbonate solution, andthen the organic layer was collected by separation. The organic layerwas dried over anhydrous sodium sulfate, and the solvent was distilledoff under reduced pressure to give the title compound (0.42 g) as acolorless powder.

NMR (CDCl₃) δ: 1.43 (9H, m), 2.60-4.89 (l1H, m), 7.59 (1H, dd, J=1.8,2.0), 7.89-7.96 (4H, m), 8.48 (1H, s).

43c) tert-Butyl1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxylate

The compound (0.42 g) obtained in Example 32b),N-((2Z)-4-(chloromethyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminehydrochloride (0.19 g) and potassium carbonate (0.37 g) were suspendedin DMF (5 mL) and mixed at 100° C. for 3 hours. The reaction solutionwas concentrated under reduced pressure, and the residue was dilutedwith a saturated aqueous sodium bicarbonate solution and ethyl acetate.The organic layer was collected by separation, and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified with a silica gel column to give the titlecompound (0.14 g) as a colorless powder.

NMR (CDCl₃) δ: 1.35 (9H, m), 1.90-6.36 (20H, m), 7.59 (1H, dd, J=9.0,2.0), 7.92-7.97 (4H,- m), 8.47 (1H, s).

43d)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)piperazine-2-carboxamide

The compound (0.14 g) obtained in Example 43c) was dissolved inconcentrated hydrochloric acid (3 mL) and mixed at room temperature for1 hour. The reaction solution was concentrated under reduced pressure,and then water was removed from the residue by azeotropy with toluene.The resulting residue was dissolved in DMF (10 mL). HOBt-NH₃ complex (53mg), WSC (66 mg) and triethylamine (0.14 g) were added thereto, and themixture was mixed at room temperature for 15 hours. The reactionsolution was concentrated under reduced pressure, and the residue wasdiluted with a saturated aqueous sodium bicarbonate solution and ethylacetate. The organic layer was collected by separation, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified with a basic silica gel column togive the title compound (50 mg) as a colorless powder.

NMR (CDCl₃) δ: 1.96-6.36 (22H, m), 7.61 (1H, dd, J=8.9, 1.9), 7.88-7.98(4H, m), 8.47 (1H, s).

Example 44 Methyl1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(5,6-dihydroimidazo[2,1-b][1,3]thiazol-3-ylmethyl)piperazine-2-carboxylate

44a) 3-Methyl 1-tert-butyl4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)piperazine-1,3-dicarboxylate

In the same manner as in Example 43a), the title compound (1.00 g) as acolorless powder was obtained from 3-methyl 1-tert-butylpiperazine-1,3-dicarboxylate (2.80 g).

NMR (CDCl₃) δ: 1.44-1.45 (9H, m), 2.70-5.03 (14H, m), 7.57-7.61 (1H, m),7.88-7.96 (4H, m), 8.46 (1H, s).

44b) Methyl1-(3-((6-chloro-2-naphthyl)sulfonyl)-propanoyl)-4-(5,6-dihydroimidazo[2,1-b][1,3]thiazol-3-ylmethyl)piperazine-2-carboxylate

The compound (0.50 g) obtained in Example 44a) was dissolved inconcentrated hydrochloric acid (3 mL) and mixed at room temperature for3 hours. The reaction solution was concentrated under reduced pressure,and then water was removed from the residue by azeotropy with toluene.The resulting residue was dissolved in DMF (5 mL).3-(chloromethyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole hydrochloride(0.24 g) and potassium carbonate (0.32 g) were added thereto, and themixture was mixed at 100° C. for 24 hours. The reaction solution wasconcentrated under reduced pressure, and the residue was diluted with asaturated aqueous sodium bicarbonate solution and ethyl acetate. Theorganic layer was collected by separation, and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure,and the residue was purified with a basic silica gel column to give thetitle compound (40 mg) as a colorless powder.

NMR (CDCl₃) δ: 2.63-5.13 (21H, m), 7.59 (1H, dd, J=8.8, 1.8), 7.91-7.96(4H, m), 8.47 (1H, s).

Example 45N-((2Z)-4-((4-(3-((4-Bromophenyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 11b), the title compound (0.72 g) aswhite crystals was obtained from the compound (1.5 g) obtained inExample 11a) and 3-((4-bromophenyl)sulfonyl)propanoic acid (WO 09805635;1.0 g).

NMR (CDCl₃) δ: 2.40-2.44 (4H, m), 2.82 (2H, t, J=7.8), 3.00 (3H, s),3.26 (2H, s), 3.35 (3H, s), 3.42-3.49 (4H, m), 3.56 (2H, t, J=5.1), 5.74(1H, s), 7.70-7.79 (4H, m).

Example 46N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

46a) tert-Butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

tert-Butyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (WO 0059502:21.0 g) and a solution of N,N′-dimethylthiourea (6.0 g) in ethanol (300mL) were heated under reflux. The reaction solution was concentrated,and the residue was dissolved in ethyl acetate and water. The aqueouslayer was collected by separation. The aqueous layer was basified withan aqueous potassium carbonate solution, and extracted with chloroform.The extract was dried over anhydrous sodium sulfate, and then thesolvent was distilled off to give the title compound (12.2 g) as a paleyellow solid.

NMR (CDCl₃) δ: 1.47 (9H, s), 1.46-1.55 (2H, m), 1.83-1.87 (2H, m), 2.55(1H, m), 2.78 (2H, m), 2.98 (3H, s), 3.23 (3H, s), 4.14 (2H, br), 6.17(1H, s).

46b)N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

To the compound (0.55 g) obtained in Example 46a) was added concentratedhydrochloric acid (4 mL), and the mixture was mixed. After completion ofexpansion, the mixture was diluted with ethanol and concentrated. To theresidue were added triethylamine (0.49 mL) and DBU (0.54 mL), and themixture was dissolved in acetonitrile (10 mL). The resulting solutionwas added to a suspension of 3-((6-chloro-2-naphthyl)sulfonyl)propanoicacid (0.53 g), WSC (0.50 g) and HOBt (0.40 g) in acetonitrile (10 mL)and mixed for 12 hours. The reaction solution was concentrated, and theresidue was dissolved in chloroform and a saturated aqueous sodiumbicarbonate solution to separate and collect the organic layer. Thesolvent was distilled off, and the residue was purified with silica gelchromatography to give the title compound (0.61 g) as a colorless solid.

NMR (CDCl₃) δ: 1.36-1.54 (2H, m), 1.86-1.94 (2H, m), 2.57-2.68 (2H, m),2.86-2.92 (2H, m), 2.98 (3H, s), 3.11 (1H, m), 3.25 (3H, s), 3.53-3.60(2H, m), 3.88 (1H, d, J=14.4), 4.53 (1H, d, J=14.4), 6.18 (1H, s), 7.59(1H, dd, J=7.8, 8.7), 7.90-8.00 (4H, m), 8.48 (1H, s).

Example 472-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole

47a) tert-Butyl4-(5,6-dihydroimidazo[2,1-b][1,3]thiazol-2-yl)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (1.46 g) wasobtained from tert-butyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate(2.0 g) and ethylenethiourea (0.79 g) by using DMF as a solvent.

NMR (CDCl₃) δ: 1.36-1.56 (2H, m), 1.46 (9H, s), 1.78-1.94 (2H, m), 2.47(1H, m), 2.71-2.85 (2H, m), 3.42-3.55 (2H, m), 3.62 (2H, m), 4.14 (2H,br), 5.91 (1H, s).

47b)2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole

In the same manner as in Example 46b), the title compound (0.18 g) as awhite solid was obtained from the compound (0.50 g) obtained in Example47a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.53 g).

NMR (CDCl₃) δ: 1.40-1.46 (2H, m), 1.76-2.20 (2H, m), 2.60 (1H, m), 2.71(1H, m), 2.81-2.90 (2H, m), 3.11 (1H, m), 3.49-3.65 (2H, m), 3.89 (1H,br), 4.10 (2H, t, J=9.4), 4.29 (2H, t, J=9.4), 4.59 (1H, br), 6.46 (1H,s), 7.59 (1H, dd, J=2.0, 8.8), 7.87-7.99 (4H, m), 8.48 (1H, s).

Example 482-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine

48a) tert-Butyl4-(6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-yl)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (1.28 g) wasobtained by using DMF as a solvent from tert-butyl4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (3.0 g) andpropylenethiourea (0.90 g).

NMR (CDCl₃) δ: 1.36-1.56 (2H, m), 1.46 (9H, s), 1.78-1.94 (4H, m), 2.47(1H, m), 2.75 (2H, t, J=12.0), 3.44 (2H, t, J=5.4), 3.62 (2H, t, J=5.4),4.14 (2H, br), 5.91 (1H, s).

48b)2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine

In the same manner as in Example 46b), the title compound (0.18 g) as awhite solid was obtained from the compound (0.50 g) obtained in Example48a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.50 g).

NMR (CDCl₃) δ: 1.25-1.52 (2H, m), 1.82-1.98 (4H, m), 2.52-2.65 (2H, m),2.87 (2H, dd, J=6.3, 9.7), 3.08 (1H, m), 3.42-3.50 (2H, m), 3.50-3.61(2H, m), 3.63-3.71 (2H, m), 3.84 (1H, d, J=13.6), 4.52 (1H, d, J=13.6),5.94 (1H, s), 7.59 (1H, dd, J=1.9, 8.6), 7.88-7.98 (4H, m), 8.47 (1H,s).

Example 49N-((2Z)-5-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

49a) tert-Butyl 4-(2-bromo-3-oxopropyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate(Wityak J., et al., J. Med. Chem., 40, p. 50 (1997): 27.6 g) in diethylether was added dibromobarbituric acid (17.0 g), and the mixture wasmixed for 12 hours. The insolubles were filtered off, and the filtratewas diluted with diethyl ether, sequentially washed with a saturatedaqueous sodium bicarbonate solution and saturated brine, and then driedover anhydrous sodium sulfate. The solvent was distilled off to give thetitle compound (31.8 g) as a pale yellow viscous oily matter.

NMR (CDCl₃) δ: 1.07-1.27 (2H, m), 1.46 (9H, s), 1.64-1.94 (5H, m),2.65-2.78 (2H, m), 4.05 (2H, br), 4.25 (1H, m), 9.45 (1H, s).

49b) tert-Butyl4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)piperidine-1-carboxylate

A solution of the compound (2.0 g) obtained in Example 49a) andN,N′-dimethylthiourea (0.55 g) in ethanol (20 mL) was heated underreflux. The reaction solution was concentrated under reduced pressure,and the residue was dissolved in water and washed with ethyl acetate.The aqueous phase was basified with an aqueous potassium carbonatesolution, and then extracted with chloroform. The extract was dried overanhydrous sodium sulfate and concentrated under reduced pressure to givethe title compound (0.56. g)

NMR (CDCl₃) δ: 1.06-1.16 (2H, m), 1.45 (9H, s), 1.60 (1H, m), 1.68 (2H,d, J=15.0), 2.36 (2H, d, J=6.9), 2.68 (2H, t, J=12.6), 2.98 (3H, s),3.21 (3H, s), 4.10 (2H, br), 6.17 (1H, s).

49c)N-((2Z)-5-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

To the compound (0.44 g) obtained in Example 49b) was added concentratedhydrochloric acid (4 mL). After completion of expansion, the mixture wasdiluted with ethanol and concentrated under reduced pressure. To theresidue were added triethylamine (0.37 mL) and DBU (0.41 mL), and themixture was dissolved in acetonitrile (10 mL). The resulting solutionwas added to a suspension of 3-((6-chloro-2-naphthyl)sulfonyl)propanoicacid (0.40 g), WSC (0.39 g) and HOBt (0.31 g) in acetonitrile (10 mL)and mixed for 12 hours. The reaction solution was concentrated underreduced pressure, and to the residue was added a saturated aqueoussodium hydrogen carbonate solution, and extracted with chloroform. Thesolvent was distilled off under reduced pressure, and the residue waspurified with silica gel chromatography to give the title compound (0.46g) as a pale yellow solid.

NMR (CDCl₃) δ: 0.95-1.10 (2H, m), 1.62-1.82 (3H, m), 2.35 (2H, d,J=6.9), 2.49 (1H, t, J=10.5), 2.83-2.89 (2H, m), 2.98 (3H, s), 2.99 (1H,t, J=10.5), 3.22 (3H, s), 3.50-3.61 (2H, m), 3.81 (1H, d, J=13.2), 4.48(1H, d, J=13.2), 6.17 (1H, s), 7.58 (1H, dd, J=1.8, 8.7), 7.88-7.95 (4H,m), 8.47 (1H, s).

Example 502-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine

50a) tert-Butyl4-(6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidin-2-ylmethyl)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (0.46 g) wasobtained from tert-butyl 4-(2-bromo-3-oxopropyl)piperidine-1-carboxylate(2.0 g) obtained in Example 49a) and propylenethiourea (0.61 g) by usingDMF as a solvent.

NMR (CDCl₃) δ: 1.01-1.15 (2H, m), 1.45 (9H, s), 1.52 (1H, m), 1.66-1.87(4H, m), 2.31 (2H, d, J=7.2), 2.67 (2H, m), 3.73 (2H, t, J=9.3), 4.11(2H, m), 4.16 (2H, t, J=9.3), 6.17 (1H, s).

50b)2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine

In the same manner as in Example 46b), the title compound (0.08 g) as apale yellow solid was obtained from the compound (0.45 g) obtained inExample 50a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.40g).

NMR (CDCl₃) δ: 0.89-1.15 (2H, m), 1.66-1.87 (5H, m), 2.34 (2H, d,J=6.8), 2.47 (1H, m), 2.98 (1H, s), 3.47-3.67 (4H, m), 3.71-3.87 (3H,m), 4.47 (1H, d, J=13.5), 6.09 (1H, s), 7.60 (1H, dd, J=1.9, 8.6),7.88-7.98 (4H, m), 8.47 (1H, s).

Example 512-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole

51a) tert-Butyl4-(5,6-dihydroimidazo[2,1-b][1,3]thiazol-2-ylmethyl)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (0.41 g) wasobtained from tert-butyl 4-(2-bromo-3-oxopropyl)piperidine-1-carboxylate(2.0 g) obtained in Example 49a) and ethylenethiourea (0.54 g) by usingDMF as a solvent.

NMR (CDCl₃) δ: 1.01-1.15 (2H, m), 1.45 (9H, s), 1.52 (1H, m), 1.69 (2H,d, J=12.6), 2.31 (2H, d, J=7.2), 2.67 (2H, m), 3.73 (2H, t, J=9.3), 4.11(2H, m), 4.16 (2H, t, J=9.3), 6.17 (1H, s).

51b)2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-5,6-dihydroimidazo[2,1-b][1,3]thiazole

In the same manner as in Example 46b), the title compound (0.09 g) as apale yellow solid was obtained from the compound (0.43 g) obtained inExample 51a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.40g).

NMR (CDCl₃) δ: 0.93-1.17 (2H, m), 1.57-1.83 (3H, m), 3.30 (2H, d,J=6.6), 2.48 (1H, t, J=12.8), 2.81-2.89 (2H, m), 2.99 (1H, t, J=12.8),3.51-3.60 (2H, m), 3.69-3.86 (3H, m), 4.10-4.20 (2H, m), 4.49 (1H, d,J=12.8), 6.19 (1H, s), 7.59 (1H, dd, J=1.8, 10.8), 7.88-7.97 (4H, s),8.47 (1H, s).

Example 52N-((2Z)-5-(1-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminedihydrochloride

52a) tert-Butyl5-chloro-2-((3-(4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)-1-piperidinyl)-3-oxopropyl)sulfonyl)-1H-indole-1-carboxylate

In the same manner as in Example 46b), the title compound (0.72 g) as awhite solid was obtained from tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.86 g) obtained in Example 46a) and3-((1-tert-butoxycarbonyl)-5-chloro-1H-indol-2-yl)sulfonylpropanoic acid(1.07 g).

NMR (DMSO-d₆) δ: 1.12-1.34 (2H, m), 1.64 (9H, s), 1.75-1.92 (2H, m),2.61 (1H, m), 2.69-2.82 (2H, m), 2.90-3.02 (5H, m), 3.58 (1H, s),3.62-3.81 (2H, m), 3.84 (1H, br), 4.23 (1H, br), 7.15 (1H, d, J=1.3),7.33 (1H, dd, J=2.1, 8.9), 7.52 (1H, d, J=8.9), 7.77 (1H, d, J=2.1).

52b)N-((2Z)-5-(1-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminedihydrochloride

To the compound (0.72 g) obtained in Example 52a) was added concentratedhydrochloric acid (5 mL), and the mixture was mixed. After completion ofexpansion, the mixture was concentrated by adding ethanol. The residuewas washed with diethyl ether and dried to give the title compound (0.68g) as a white solid.

NMR (DMSO-d₆) δ: 1.09 (1H, m), 1.43 (1H, m), 1.77-1.93 (2H, m), 2.59(1H, m), 2.69-2.82 (2H, m), 2.90-3.02 (5H, m), 3.60 (3H, s), 3.62-3.74(2H, m), 3.84 (1H, br), 4.23 (1H, br), 7.15 (1H, d, J=1.3), 7.33 (1H,dd, J=2.1, 8.9), 7.52 (1H, d, J=8.9), 7.77 (1H, d, J=2.1), 10.10 (1H, d,J=4.3), 12.62 (1H, d, J=1.3).

Example 536-Chloro-N-(2-(4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)-1-piperidinyl)-2-oxoethyl)-2-naphthalenesulfonamide

In the same manner as in Example 46b), the title compound (0.17 g) as acolorless solid was obtained fromN-((6-chloro-2-naphthyl)sulfonyl)glycine (0.30 g) and tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.30 g) obtained in Example 46a).

NMR (DMSO-d₆) δ: 1.04(1H, m), 1.31 (1H, m), 1.64-1.80 (2H, m), 2.52-2.67(2H, m), 2.82 (3H, s), 2.97 (1H, m), 3.12 (3H, s), 3.69-3.84 (3H, m),4.13 (1H, d), 6.58 (1H, s), 7.64 (1H, dd, J=2.1, 8.6), 7.89 (1H, s),8.09 (1H, d, J=8.6), 8.13-8.23 (2H, m), 8.48 (1H, s).

Example 542-(((6-Chloro-2-naphthyl)sulfonyl)(2-(4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)-1-piperidinyl)-2-oxoethyl)amino)acetamide

In the same manner as in Example 46b), the title compound (0.30 g) as acolorless solid was obtained fromN-(2-amino-2-oxoethyl)-N-((6-chloro-2-naphthyl)sulfonyl)glycine (0.34 g)and tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.30 g) obtained in Example 46a).

NMR (DMSO-d₆) δ: 1.18 (1H, m), 1.47 (1H, m), 1.72-1.86 (2H, m),2.59-2.74 (2H, m), 2.82 (3H, s), 3.08 (1H, m), 3.13 (3H, s), 3.77-3.91(3H, m), 4.24-4.37 (3H, m), 6.65 (1H, s), 7.14 (1H, s), 7.68 (1H, dd,J=1.8, 8.8), 7.88-8.01 (2H, m), 8.11 (1H, m), 8.17-8.25 (2H, m), 8.56(1H, d, J=1.3).

Example 55N-((2Z)-5-(1-(3-(((E)-2-(4-Chlorophenyl)vinyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 46b), the title compound (0.33 g) as acolorless solid was obtained from3-(((E)-2-(4-chlorophenyl)vinyl)sulfonyl)propanoic acid (0.27 g) andtert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.3 g) obtained in Example 46a).

NMR (CDCl₃) δ: 1.30-1.57 (2H, m), 1.83-1.99 (2H, m), 2.57-2.70 (2H, m),2.81-2.94 (2H, m), 2.98 (3H, s), 3.11 (1H, m), 3.24 (3H, s), 3.41-3.56(2H, m), 3.88 (1H, d, J=13.0), 4.58 (1H, d, J=13.0), 6.14 (1H, s), 6.85(1H, d, J=15.5), 7.38-7.48 (4H, m), 7.53 (1H, d).

Example 56N-((2Z)-5-(1-(3-((7-Chloro-2H-chromen-3-yl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 46b), the title compound (0.30 g) as acolorless solid was obtained from3-((7-chloro-2H-chromen-3-yl)sulfonyl)propanoic acid (0.30 g) andtert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.30 g) obtained in Example 46a).

NMR (CDCl₃) δ: 1.41-1.50 (2H, m), 1.84-1.99 (2H, m), 2.58-2.70 (2H, m),2.80-2.91 (2H, m), 2.98 (3H, s), 3.12 (1H, m), 3.25 (3H, s), 3.41-3.55(2H, m), 3.87 (1H, d, J=13.6), 4.58 (1H, d, J=13.6), 5.03 (2H, s), 6.16(1H, s), 6.90-6.98 (2H, m), 7.10 (1H, d, J=8.1), 7.32 (1H, s)

Example 57 Allyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidenecarbamate

57a) tert-Butyl 4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (3.9 g) as apale yellow solid was obtained from tert-butyl4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (8.0 g) and thiourea (2.4g).

NMR (CDCl₃) δ: 1.45 (9H, s), 1.46-1.66 (2H, m), 1.91 (2H, d, J=11.8),2.80 (3H, m), 4.15 (2H, d, J=14.2), 4.81 (2H, s), 6.76 (1H, s).

57b) tert-Butyl4-(2-imino-3-methyl-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

To a solution of the compound (1.0 g) obtained in Example 57a) in DMF(5.0 mL), methyl iodide (0.44 mL) was added, and the mixture was mixedat 80° C. for 2 hours. The reaction solution was concentrated, and theresidue was dissolved in chloroform and a saturated aqueous sodiumbicarbonate solution and mixed for 15 minutes. The organic layer wascollected by separation, and dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the residue was purified with a silicagel chromatography to give the title compound (0.52 g) as a pale yellowsolid.

NMR (CDCl₃) δ: 1.33-1.53 (2H, m), 1.46 (9H, s), 1.80 (2H, d, J=12.0),2.49 (1H, m), 2.75 (2H, t, J=11.4), 3.23 (3H, s), 4.14 (2H, d, J=12.8),6.05 (1H, s).

57c) tert-Butyl4-((2Z)-2-(((allyloxy)carbonyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

To a solution of the compound (0.47 g) obtained in Example 57b) indichloromethane (10 mL), triethylamine (0.23 mL) and allyl chloroformate(0.18 mL) were added with ice cooling, and mixed for 1 hour. Afteradding the ice chips to the reaction solution and mixing for 15 minutes,the reaction solution was diluted with chloroform and a saturatedaqueous sodium bicarbonate solution. The organic layer was collected byseparation, and dried over anhydrous sodium sulfate. The solvent wasdistilled off to give the title compound (0.60 g) as a white solid.

NMR (CDCl₃) δ: 1.46 (9H, s), 1.48-1.89 (2H, m), 1.91 (2H, bd, J=9.0),2.67-2.88 (3H, m), 3.60 (3H, s), 4.15 (2H, br), 4.69 (2 h, m), 5.21 (1H,m), 5.35 (1H, m), 6.03 (1H, m), 6.52 (1H, s).

57d) Allyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidenecarbamate

The compound (0.68 g) obtained in Example 57c) was dissolved in a 4 Nsolution of hydrochloride in dioxane (10 mL), and mixed for 6 hours. Thereaction solution was neutralized with a saturated aqueous sodiumbicarbonate solution and extracted with chloroform. After distilling offthe solvent, triethylamine (0.50 mL) was added to the residue, and themixture was dissolved in acetonitrile (10 mL). This solution was addedto a suspension of 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.53g), WSC (0.51 g) and HOBt (0.41 g) in acetonitrile (10 mL), and mixedfor 12 hours. The reaction solution was concentrated, and the residuewas dissolved in chloroform and a saturated aqueous sodium bicarbonatesolution. The organic layer was collected by separation, and dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas purified with a silica gel column to give the title compound (0.88g) as a colorless solid.

NMR (CDCl₃) δ: 1.41-1.53 (2H, m), 1.91-2.06 (2H, m), 2.64 (1H, m), 2.75(1H, m), 2.88 (2H, t, J=8.6), 3.14 (1H, m), 3.56 (2H, t, J=8.6), 3.61(3H, s), 3.92 (1H, d, J=13.4), 4.56 (1H, d, J=13.4), 4.70 (2H, m), 5.23(1H, m), 5.36 (1H, m), 6.02 (1H, m), 6.52 (1H, s).

Example 585-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-imine

To a solution of allyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidenecarbamate(0.60 g) obtained in Example 57d) in THF, 1,3-dimethylbarbituric acid(0.25 g) and tetrakis(triphenylphosphine)palladium (0.06 g) were addedthereto and mixed for 12 hours under argon atmosphere. The insolubleswere filtered off, and the filtrate was concentrated. The residue waspurified with a silica gel column to give the title compound (0.32 g) asa pale yellow solid.

NMR (CDCl₃) δ: 1.28-1.50 (2H, m), 1.82-1.94 (2H, m), 2.55-2.64 (2H, m),2.85-2.90 (2H, m), 3.08 (1H, t, J=12.6), 3.23 (3H, s), 3.52-3.58 (2H,m), 3.87 (1H, d, J=13.5), 4.51 (1H, d, J=13.5), 6.03 (1H, s), 7.58 (1H,dd, J=1.8, 8.8), 7.88-7.95 (4H, m), 8.47 (1H, s).

Example 59 Allyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-ethyl-1,3-thiazol-2(3H)-ylidenecarbamate

59a) tert-Butyl4-(3-ethyl-2-imino-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 57b), the title compound (0.48 g) wasobtained from tert-butyl4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate (1.0 g) obtained inExample 57a) and ethyl iodide (0.73 mL).

NMR (CDCl₃) δ: 1.24 (3H, t, J=7.4), 1.33-1.54 (2H, m), 1.46 (9H, s),1.80 (2H, d, J=12.0), 2.49 (1H, m), 2.75 (2H, t, J=11.4), 4.14 (2H, d,J=12.8), 4.11 (2H, q, J=7.4), 6.05 (1H, s).

59b) tert-butyl4-((2Z)-2-(((allyloxy)carbonyl)imino)-3-ethyl-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 57c), the title compound (0.60 g) wasobtained from the compound (0.48 g) obtained in Example 59a).

NMR (CDCl₃) δ: 1.26 (3H, t, J=7.4), 1.47 (9H, s), 1.47-1.63 (2H, m),1.92 (2H, d, J=11.2), 2.67-2.87 (3H, m), 4.11 (2H, q, J=7.4), 4.17 (2H,br), 4.69 (2H, m), 5.21 (1H, d, J=12.0), 5.35 (1H, d, J=17.2), 6.03 (1H,m), 6.56 (1H, s).

59c) Allyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-ethyl-1,3-thiazol-2(3H)-ylidenecarbamate

In the same manner as in Example 57d), the title compound (0.69 g) wasobtained from the compound (0.54 mg) obtained in Example 59b) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.40 g).

NMR (CDCl₃) δ: 1.36 (3H, s, J=7.2), 1.39-1.55 (2H, m), 1.92-2.05 (2H,m), 2.64 (1H, m), 2.76 (1H, m), 2.89 (2H, t, J=8.0), 3.14 (1H, t,J=12.8), 3.57 (2H, t, J=8.0), 3.82 (1H, d, J=13.2), 4.10 (2H, q, J=7.2),4.70 (2H, m), 5.22 (1H, m), 5.35 (1H, m), 6.03 (1H, m), 6.55 (1H, s),7.60 (2H, dd, J=2.2, 8.8), 7.89-7.94 (4H, m), 8.49 (1H, s)

Example 605-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-ethyl-1,3-thiazol-2(3H)-imine

In the same manner as in Example 58), the title compound (0.33 g) wasobtained from allyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)-3-ethyl-1,3-thiazol-2(3H)-ylidenecarbamate(0.50 g) obtained in Example 59c).

NMR (CDCl₃) δ: 1.29 (3H, t, J=7.2), 1.24-1.44 (2H, m), 1.80-1.96 (4H,m), 2.50-2.65 (2H, m), 2.78-2.93 (2H, m), 3.08 (1H, m), 3.48-3.62 (2H,m), 3.71 (2H, q, J=7.2), 3.85 (1H, d, J=13.6), 4.53 (1H, d, J =13.6),6.10 (1H, s), 7.59 (1H, dd, J=1.9, 8.6), 7.88-7.97 (4H, m), 8.47 (1H,s).

Example 61N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)acetamide

To a solution of5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)-3-methyl-1,3-thiazol-2(3H)-imine(0.20 g) obtained in Example 58) in dichloromethane (5 mL),triethylamine (0.5 mL) and acetic anhydride (0.5 mL) were added andmixed for 2 hours. After adding ice chips to the reaction solution andmixing for 15 minutes, the reaction solution was diluted with chloroformand a saturated aqueous sodium bicarbonate solution. The organic layerwas collected by separation, and dried over anhydrous sodium sulfate.The solvent was distilled off, and the residue was purified with asilica gel column to give the title compound (0.22 g) as a white solid.

NMR (CDCl₃) δ: 1.40-1.59 (2H, m), 1.93-2.06 (2H, m), 2.29 (3H, s), 2.64(1H, t, J=12.9), 2.81 (1H, m), 2.89 (2H, m), 3.13 (1H, t, J=12.9), 3.56(2H, m), 3.67 (3H, s), 3.90 (1H, d, J=12.3), 4.56 (1H, d, J=12.3), 6.55(1H, s), 7.58 (1H, dd, J=1.8, 8.7), 7.88-7.95 (4H, m), 8.47 (1H, s).

Example 62N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-propylamine

62a) tert-Butyl4-(2-(propylamino)-1,3-thiazol-5-yl)piperidine-1-carboxylate

In same manner as in Example 46a), the title compound (1.24 g) as a paleyellow solid was obtained from tert-butyl4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (6.45 g) andN-propylthiourea (2.0 g).

NMR (CDCl₃) δ: 0.98 (3H, t, J=7.2), 1.47 (9H, s), 1.50-1.72 (4H, m),1.92 (2H, m), 2.80 (3H, m), 3.20 (2H, t, J=7.2), 4.15 (2H, d, J=14.2),5.23 (1H, s), 6.78 (1H, s)

62b)5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-N-propyl-1,3-thiazol-2-amine

In the same manner as in Example 46b), the title compound (1.74 g) wasobtained from the compound (1.27 g) obtained in Example 62a) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (1.12 g).

NMR (CDCl₃) δ: 1.37-1.60 (2H, m), 1.91-2.04 (2H, m), 2.63 (1H, t,J=12.9), 2.83-2.91 (3H, m), 3.11 (1H, t, J=12.9), 3.53-3.60 (2H, m),3.87 (1H, d, J=14.1), 4.51 (1H, d, J=14.1), 4.80 (2H, s), 6.74 (1H, s),7.57 (1H, dd, J=1.8, 8.2), 7.88-7.95 (4H, m), 8.47 (1H, s).

62c)N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H))-ylidene)-N-propylamine

In the same manner as in Example 57b), the title compound (0.28 g) wasobtained from the compound (0.50 g) obtained in Example 62b) and methyliodide (0.61 mL).

NMR (CDCl₃) δ: 0.97 (3H, t, J=7.2), 1.35-1.50 (2H, m), 1.63-1.73 (2H,m), 1.84-1.96 (2H, m), 2.57-2.65 (2H, m), 2.88 (2H, dd, J=6.6, 9.9),3.01 (2H, t, J=7.2), 3.09 (1H, t, J=12.3), 3.22 (3H, s), 3.53-3.59 (1H,m), 3.86 (1H, d, J=12.9), 4.51 (1H, d, J=12.9), 6.11 (1H, s), 7.58 (1H,dd, J=1.8, 8.1), 7.88-7.95 (4H, m), 8.46 (1H, s).

Example 63N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-ethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

63a) tert-Butyl4-(2-(methylamino)-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (1.74 g) as apale yellow solid was obtained from tert-butyl4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (6.45 g) andN-methylthiourea (1.53 g).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.57 (2H, m), 1.92 (2H, dd, J=14.9), 2.80(3H, m), 2.95 (3H, s), 4.15 (2H, d, J=13.6), 5.23 (1H, s), 6.80 (1H, s).

63b)5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-N-methyl-1,3-thiazol-2-amine

In the same manner as in Example 46b), the title compound (2.36 g) as apale yellow solid was obtained from the compound (1.74 g) obtained inExample 63a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (1.66g).

NMR (CDCl₃) δ: 1.37-1.61 (2H, m), 1.91-2.04 (2H, m), 2.63 (1H, t,J=13.2), 2.83-2.92 (3H, m), 2.95 (3H, s), 3.12 (1H, t, J=13.2),3.52-3.60 (2H, m), 3.85 (1H, d, J=13.5), 4.53 (1H, d, J=13.5), 4.94 (1H,s), 6.78 (1H, s), 7.58 (1H, dd, J=1.8, 7.8), 7.88-7.95 (4H, m), 8.47(1H, s).

63c)N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-ethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 57b), the title compound (0.29 g) as apale yellow solid was obtained from the compound (0.50 g) obtained inExample 63b) and ethyl iodide (0.21 mL).

NMR (CDCl₃) δ: 1.25 (3H, t, J=7.2), 1.35-1.53 (2H, m), 1.84-1.99 (2H,m), 2.56-2.67 (2H, m), 2.88 (2H, t, J=7.0), 2.97 (3H, s), 3.10 (1H, m),3.48 (2H, t, J=7.0), 3.68 (2H, q, J=7.2), 3.88 (1H, d, J=13.2), 4.52(1H, d, J=13.2), 6.20 (1H, s), 7.59 (1H, dd, J=2.2, 9.2), 7.88-7.97 (4H,m), 8.48 (1H, s).

Example 642-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-2-(methylimino)-1,3-thiazol-3(2H)-yl)ethanol

In the same manner as in Example 57b), the title compound (0.36 g) as apale yellow solid was obtained from5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-N-methyl-1,3-thiazol-2-amine(0.60 g) obtained in Example 63b) and 2-iodoethanol (0.20 mL).

NMR (CDCl₃) δ: 1.36-1.51 (2H, m), 1.85-1.98 (2H, m), 2.56-2.68 (2H, m),2.86-2.89 (2H, m), 2.92 (3H, s), 3.10 (1H, m), 3.53-3.59 (2H, m),3.81-3.91 (5H, m), 4.54 (1H, d, J=14.8), 6.16 (1H, s), 7.58 (1H, dd,J=1.8, 7.8), 7.88-7.95 (4H, m), 8.47 (1H, s).

Example 652-(5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-2-imino-1,3-thiazol-3(2H)-yl)-acetamide

65a)5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-1,3-thiazol-2-amine

In the same manner as in Example 46b), the title compound (0.86 g) as apale yellow solid was obtained from tert-butyl4-(2-amino-1,3-thiazol-5-yl)piperidine-1-carboxylate (1.83 g) obtainedin Example 57a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid(1.93 g).

NMR (CDCl₃) δ: 1.37-1.60 (2H, m), 1.91-2.04 (2H, m), 2.63 (1H, t,J=12.9), 2.83-2.91 (3H, m), 3.11 (1H, t, J=12.9), 3.53-3.60 (2H, m),3.87 (1H, d, J=14.1), 4.51 (1H, d, J=14.1), 4.80 (2H, s), 6.74 (1H, s),7.57 (1H, dd, J=1.8, 8.2), 7.88-7.95 (4H, m), 8.47 (1H, s).

65b)2-(5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-2-imino-1,3-thiazol-3(2H)-yl)acetamide

In the same manner as in Example 57b),the title compound (0.24 g) as apale yellow solid was obtained from the compound (0.50 g) obtained inExample 65a) and iodoacetamide (0.24 g).

NMR (CDCl₃) δ: 1.32-1.51 (2H, m), 1.82-1.95 (2H, m), 2.54-2.63 (2H., m),2.85-2.90 (2H, m), 3.08 (1H, t, J=11.7), 3.52-3.58 (2H, m), 3.87 (1H, d,J=13.8), 4.27 (2H, s), 4.53 (1H, d, J=13.8), 5.35 (1H, s), 6.18 (1H, s),7.25 (1H, s), 7.58 (1H, dd, J=1.8, 8.8), 7.88-7.95 (4H, m), 8.47 (1H,s).

Example 662-(((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)ethanol

66a) N-(2-((tert-Butyldimethylsilyl)oxy)ethyl)thiourea

To a solution of 2-((tert-butyldimethylsilyl)oxy)ethanamine (WO 0007985:24.4 g) in THF (300 mL) was added benzoyl isothiocyanate (22.7 g), andthe mixture was mixed for 2 hours. The reaction solution wasconcentrated, and the residue was dissolved in methanol (150 mL). To theresulting solution were added potassium carbonate (5.0 g) and water (50mL), and the mixture was mixed for 2 hours. The insolubles were filteredoff, and the filtrate was concentrated. The residue was dissolved inethyl acetate, sequentially washed with 1 N hydrochloric acid, asaturated aqueous sodium bicarbonate solution and saturated brine, andthen dried over anhydrous sodium sulfate. The solvent was distilled offto give the title compound (27.7 g) as a colorless oily matter.

NMR (CDCl₃) δ: 0.02 (6H, s), 0.83 (9H, s), 1.74 (1H, s), 3.28 (2H, br),3.68-3.73 (2H, m), 6.05 (1H, br), 6.56 (1H, br), 6.98 (1H, br).

66b) tert-Butyl4-(2-((2-hydroxyethyl)amino)-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 47a), the title compound (1.52 g) wasobtained from the compound (2.34 g) obtained in Example 66a) andtert-butyl 4-(1-bromo-2-oxoethyl)piperidine-1-carboxylate (4.6 g).

NMR (CDCl₃) δ: 1.46 (9H, s), 1.46-1.60 (2H, m), 1.90 (2H, d, J=11.4),2.74-2.83 (3H, m), 3.46 (2H, t, J=5.4), 3.81 (2H, t, J=5.4), 4.43 (1H,m), 6.75 (1H, s).

66c)2-((5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-1,3-thiazol-2-yl)amino)ethanol

In the same manner as in Example 46b), the title compound (1.37 g) wasobtained from the compound (1.26 g) obtained in Example 66b) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (1.15 g).

NMR (CDCl₃) δ: 1.31-1.62 (2H, m), 1.88-2.03 (2H, m), 2.62 (1H, t,J=12.6), 2.80-2.93 (3H, m), 3.11 (1H, t, J=12.6), 3.45 (2H, t, J=5.4),3.53-3.61 (2H, m), 3.81 (2H, t, J=5.4), 3.84 (1H, d, J=13.4), 4.51 (1H,d, J=13.4), 5.55 (1H, br), 6.74 (1H, s), 7.58 (1H, dd, J=2.0, 7.8),7.88-7.96 (4H, m), 8.47 (1H, s).

66d)2-(((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)ethanol

In the same manner as in Example 57b), the title compound (0.75 g) wasobtained from the compound (1.0 g) obtained in Example 66c) and methyliodide (0.25 mL).

NMR (CDCl₃) δ: 1.35-1.51 (2H, m), 1.82-1.98 (2H, m), 2.55-2.69 (2H, m),2.88 (2H, dd, J=6.3, 9.7), 3.09 (1H, m), 3.15 (2H, t, J=5.3), 3.25 (3H,s), 3.51-3.64 (2H, m), 3.82 (2H, t, J=5.3), 3.86 (1H, d, J=13.8), 4.53(1H, d, J=13.8), 6.18 (1H, s), 7.59 (1H, dd, J=2.0, 8.8), 7.89-7.98 (4H,m), 8.48 (1H, s).

Example 67(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carbaldehyde

67a) tert-Butyl4-((2Z)-4-formyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(5.0 g) obtained in Example 46a) in THF (75 mL) was added n-butyllithium(24 mL, a 1.6 M hexane solution) at −78° C. The reaction solution wasmixed for 15 minutes, and then DMF (5 mL) was added thereto, and themixture was further mixed for 30 minutes. To the reaction solution wasadded a saturated aqueous ammonium chloride solution, and then pouredinto a mixed solution of ethyl acetate and a saturated aqueous sodiumbicarbonate solution. The organic layer was collected by separation,washed with saturated brine, and then dried over anhydrous sodiumsulfate. The solvent was distilled off, and the residue was purifiedwith a silica gel column to give the title compound (3.45 g) as a yellowsolid.

NMR (CDCl₃) δ: 1.48 (9H, s), 1.55-1.76 (2H, m), 1.84 (2H, d, J=11.7),2.78 (2H, m), 3.04 (3H, s), 3.43 (1H, m), 3.57 (3H, s), 4.25 (2H, br),9.77 (1H, s).

67b)(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carbaldehyde

In the same manner as in Example 46b), the title compound (1.89 g) as apale yellow solid was obtained from the compound (1.07 g) obtained inExample 67a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.55-1.73 (2H, m), 1.86-1.97 (2H, m), 2.61 (1H, m),2.88-2.96 (2H, m), 3.03 (3H, s), 3.16 (1H, m), 3.48-3.59 (3H, m), 3.55(3H, s), 3.97 (1H, d, J=13.5), 4.67 (1H, d, J=13.5), 7.59 (1H, dd,J=1.8, 9.0), 7.89-7.96 (4H, m), 8.47 (1H, s), 9.76 (1H, s).

Example 68(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxylicacid

To a solution of(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carbaldehyde(0.20 g) obtained in Example 67b) in tert-butylalcohol/water/2-methyl-2-butene (40 mL, 5:4:1) were added sodiumchlorite (0.21 g) and sodium dihydrogen phosphate (0.28 g), and themixture was mixed for 12 hours. The reaction solution was concentrated,and the residue was dissolved in chloroform and saturated brine. Thechloroform layer was collected by separation, and dried over anhydroussodium sulfate. The solvent was distilled off to give the title compound(0.19 g) as a colorless solid.

NMR (CDCl₃) δ: 1.38-1.69 (2H, m), 1.96-2.14 (2H, m), 2.60 (1H, m),2.83-3.01 (3H, m), 3.19 (3H, s), 3.21 (1H, m), 3.53-3.61 (2H, m), 3.88(3H, s), 3.96 (1H, s), 4.64 (1H, d, J=10.4), 7.60 (1H, dd, J=1.8, 9.2),7.92-7.98 (4H, m), 8.48 (1H, s).

Example 69(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxamide

To a solution of(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxylicacid (0.21 g) obtained in Example 68) in dichloromethane (20 mL) wasadded WSC (0.11 g) and HOBt-NH₃ complex (0.09 g), and mixed for 12hours. The reaction solution was diluted with chloroform, washed with asaturated aqueous sodium bicarbonate solution, and dried over anhydroussodium sulfate. The solvent was distilled off, and the residue waspurified with a silica gel column to give the title compound (0.07 g) asa colorless solid.

NMR (CDCl₃) δ: 1.46-1.59 (2H, m), 1.77-1.91 (2H, m), 2.55 (1H, m),2.86-2.91 (2H, m), 2.99 (3H, s), 3.08 (1H, m), 3.18 (1H, m), 3.29 (3H,s), 3.53-3.58 (2H, m), 3.89 (1H, d, J=14.1), 4.59 (1H, d, J=14.1), 5.78(2H, br), 7.58 (1H, dd, J=1.8, 8.7), 7.88-7.96 (4H, m), 8.47 (1H, s).

Example 70(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-N-(2-hydroxyethyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxamide

In the same manner as in Example 69), the title compound (0.08 g) wasobtained from(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxylicacid (0.20 g) obtained in Example 68), WSC (0.11 g), HOBt (0.09 g) and2-aminoethanol (0.05 mL).

NMR (CDCl₃) δ: 1.47-1.90 (4H, m), 2.53 (1H, m), 2.85-2.90 (2H, m), 2.98(3H, s), 3.02-3.18 (2H, m), 3.25 (3H, s), 3.53-3.62 (4H, m), 3.81 (2H,t, J=5.1), 3.87 (1H, d, J=14.1), 4.59 (1H, d, J=14.1), 6.27 (1H, br),7.59 (1H, dd, J=1.8, 8.7), 7.89-7.97 (4H, m), 8.48 (1H, s).

Example 71(2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-N-propyl-2,3-dihydro-1,3-thiazole-4-carboxamide

In the same manner as in Example 69), the title compound (0.05 g) wasobtained from(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxylicacid (0.20 g) obtained in Example 68), WSC (0.11 g), HOBt (0.09 g) andpropylamine (0.05 mL).

NMR (CDCl₃) δ: 0.99 (3H, t, J=6.9), 1.40-1.86 (4H, m), 2.52 (1H, m),2.85-2.90 (2H, m), 2.98 (3H, s), 2.98-3.20 (3H, m), 3.23 (3H, s), 3.36(2H, q, J=6.9), 3.55-3.60 (2H, m), 3.87 (1H, d, J=14.1), 4.60 (1H, d,J=14.1), 5.78 (1H, br), 7.60 (1H, dd, J=1.8, 7.8), 7.80-7.97 (4H, m),8.48 (1H, s).

Example 721-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)ethanol

72a) tert-Butyl4-((2Z)-4-(1-hydroxyethyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.38 g) wasobtained from tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(1.0 g) obtained in Example 46a) and acetaldehyde (0.36 mL).

NMR (CDCl₃) δ: 1.39-1.83 (4H, m), 1.47 (9H, s), 1.51 (2H, d, J=6.6),2.73 (2H, m), 2.95 (1H, m), 2.97 (3H, s), 3.41 (3H, s), 4.17 (2H, m),5.03 (1H, q, J=6.6).

72b)1-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)ethanol

In the same manner as in Example 46b), the title compound (0.37 g) wasobtained from the compound (0.38 g) obtained in Example 72a) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.32 g).

NMR (CDCl₃) δ: 1.38-1.69 (2H, m), 1.96-2.14 (2H, m), 2.60 (1H, m),2.83-3.01 (3H, m), 3.19 (3H, s), 3.21 (1H, m), 3.39 (3H, s), 3.53-3.61(2H, m), 3.88 (3H, s), 3.96 (1H, s), 4.64 (1H, d, J=10.4), 7.60 (1H, dd,J=1.8, 9.2), 7.92-7.98 (4H, m), 8.48 (1H, s).

Example 731-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)ethanone

To a solution of1-((2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)ethanol(0.20 g) obtained in Example 72b) in dichloromethane (4 mL) was addedDess-Martin reagent (0.19 g) and mixed for 2 hours. The reactionsolution was diluted with chloroform, washed with a saturated aqueoussodium bicarbonate solution, and then dried over anhydrous sodiumsulfate. The solvent was distilled off, and the residue was purifiedwith a silica gel column to give the title compound (0.10 g) as acolorless solid.

NMR (CDCl₃) δ: 1.39-1.52 (2H, m), 1.83-1.96 (2H, m), 2.45 (3H, s), 2.56(1H, m), 2.81-2.95 (2H, m), 3.02 (3H, s), 3.09-3.21 (2H, m), 3.33 (3H,s), 3.50-3.65 (2H, m), 3.90 (1H, d, J=12.8), 4.59 (1H, d, J=12.8), 7.60(1H, dd, J=2.0, 8.8), 7.89-7.98 (4H, m), 8.48 (1H, s).

Example 74(2E)-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-1,3-thiazolidin-4-ylidene)acetonitrile

74a) tert-Butyl4-((2Z,4E)-4-(cyanomethylene)-3-methyl-2-(methylimino)-1,3-thiazolidin-5-yl)piperidine-1-carboxylate

To a solution of potassium tert-butoxide (1.4 g) in DME (40 mL) wasadded (p-tolylsulfonyl)methyl isocyanate (1.3 g) at −78° C. and mixedfor 15 minutes. To the reaction solution was added a solution of thecompound (2.0 g) obtained in Example 20a) in DME (20 mL). The reactionmixture was heated until the temperature reached room temperature andmixed for 1 hour. To the reaction solution was added methanol (15 mL)and further mixed at 80° C. for 1 hour. The reaction solution wasconcentrated, and the residue was dissolved in chloroform. Thechloroform solution was washed with saturated brine, and dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas purified with a silica gel column to give the title compound (0.85g) as a pale yellow solid.

NMR (CDCl₃) δ: 1.18-1.69 (4H, m), 1.45 (9H, s), 2.48 (1H, m), 2.63-2.79(2H, m), 3.11 (3H, s), 3.14 (3H, s), 4.08-4.20 (2H, m), 4.39 (1H, d,J=0.9), 4.56 (1H, d, J=3.6).

74b)(2E)-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-1,3-thiazolidin-4-ylidene)acetonitrile

In the same manner as in Example 46b), the title compound (0.74 g) wasobtained from the compound (0.55 g) obtained in Example 74a) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.26-1.43 (3H, m), 1.76 (1H, m), 2.47-2.62 (2H, m),2.83-2.90 (2H, m), 3.04-3.15 (7H, m), 3.51-3.56 (2H, m), 3.87 (1H, m),4.41 (1H, d, J=2.1), 4.60 (1H, m), 4.67 (1H, d, J=3.3), 7.59 (1H, dd,J=1.8, 8.8), 7.88-7.96 (4H, m), 8.46 (1H, s).

Example 752-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)acetamide

75a) tert-Butyl4-((2Z)-4-carbamoylmethyl-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-((2Z,4E)-4-(cyanomethylene)-3-methyl-2-(methylimino)-1,3-thiazolidin-5-yl)piperidine-1-carboxylate(0.30 g) obtained in Example 74a) in DMSO (6.0 mL) were added potassiumcarbonate (0.1 g) and a 30% aqueous hydrogen peroxide solution (1 mL) at0° C. and mixed for 30 minutes. The reaction solution was diluted withethyl acetate, washed with saturated brine, and then dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas crystallized from hexane to give the title compound (0.32 g) as acolorless solid.

NMR (CDCl₃) δ: 1.47 (9H, s), 1.56-1.71 (4H, m), 2.70-2.79 (3H, m), 2.99(3H, s), 3.23 (3H, s), 3.44 (2H, s), 4.19 (2H, br), 5.67 (2H, d,J=19.5).

75b)2-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)acetamide

In the same manner as in Example 46b), the title compound (0.43 g) as acolorless solid was obtained from the compound (0.32 g) obtained inExample 75a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (DMSO-d₆) δ: 1.06-1.19 (1H, m), 1.32-1.46 (1H, m), 1.57-1.72 (2H,m), 2.44-2.54 (3H, m), 2.63-2.77 (2H, m), 2.82 (3H, s), 2.99 (2H, t,J=11.7), 3.10 (3H, s), 3.60-3.66 (2H, m), 3.82 (1H, d, J=12.6), 4.27(1H, d, J=12.), 7.09 (1H, s), 7.54 (1H, s), 7.72 (1H, dd, J=2.1, 8.7),7.98 (1H, dd, J=2.1, 8.7), 8.17 (1H, d, J=9.0), 8.24-8.31 (2H, m), 8.63(1H, s).

Example 76N-((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-4-(1H-tetrazol-5-ylmethyl)-1,3-thiazol-2(3H)-ylidene)-N-methylamine

To a solution of the compound (0.3 g) obtained in Example 74b) intoluene (10 mL), trimethyltin azide (0.35 g) was added, and the mixturewas overheated under reflux for 24 hours. To the reaction solution,methanol (2 mL) was added, and the mixture was mixed for 1 hour. Thereaction solution was concentrated, and the residue was purified with asilica gel column to give the title compound (0.1-4 g) as a colorlesssolid.

NMR (CDCl₃) δ: 1.45-1.54 (2H, m), 1.97-2.12 (2H, m), 2.64 (1H, m),2.84-2.93 (3H, m), 3.17 (3H, s), 3.31 (1H, m), 3.55-3.60 (3H, m), 3.67(3H, s), 3.94 (1H, d, J=12.3), 4.21 (1H, d, J=4.5), 4.68 (1H, d,J=12.3), 7.60 (1H, dd, J=1.8, 8.7), 7.89-7.98 (4H, m), 8.45 (1H, s).

Example 77 Methyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-carboxylate

77a) tert-Butyl4-((2Z)-4-(methoxycarbonyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.24 g) as apale yellow viscous oily matter was obtained from tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.50 g) obtained in Example 46a) and methyl chlorocarbonate (0.25 mL).

NMR (CDCl₃) δ: 1.40-1.84 (4H, m), 1.47 (9H, s), 2.75 (2H, t, J=12.2),3.00 (3H, s), 3.39 (3H, s), 3.39 (1H, m), 3.89 (3H, s), 4.17 (2H, m).

77b) Methyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxylate

In the same manner as in Example 46b), the title compound (0.26 g) as acolorless solid was obtained from the compound (0.24 g) obtained inExample 77a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.43-1.56 (2H, m), 1.82-1.94 (2H, m), 2.51-2.59 (1H, m),2.87-2.92 (2H, m), 3.00 (3H, s), 3.10 (1H, m), 3.39 (3H, s), 3.47 (1H,m), 3.53-3.59 (2H, m), 3.90 (3H, s), 3.91 (1H, d, J=13.5), 4.62 (1H, d,J=13.5), 7.60 (1H, dd, J=2.1, 8.7), 7.90-7.97 (4H, m), 8.49 (1H, s).

Example 78 Butyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxylate

78a) tert-Butyl4-((2Z)-4-(butoxycarbonyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.91 g) as apale yellow solid was obtained from tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.80 g) obtained in Example 46a) and butyl chlorocarbonate (0.67 mL).

NMR (CDCl₃) δ: 0.96 (3H, t, J=7.5), 1.26 (2H, t, J=7.5), 1.47 (9H, s),1.44-1.83 (6H, m), 2.73 (2H, t, J=12.3), 3.00 (3H, s), 3.39 (3H, s),3.37-3.41 (1H, m), 4.25-4.34 (2H, m), 4.29 (2H, t, J=7.5).

78b) Butyl(2Z)-5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-4-carboxylate

In the same manner as in Example 46b), the title compound (0.49 g) as apale yellow solid was obtained from the compound (0.50 g) obtained inExample 78a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 0.98 (3H, t, J=7.4), 1.38-1.70 (3H, m), 1.67-1.90 (4H,m), 2.53 (1H, m), 2.87-2.99 (2H, m), 3.00 (3H, s), 3.08 (1H, m), 3.39(3H, s), 3.53-3.58 (3H, m), 3.92 (2H, d, J=13.8), 4.27 (2H, t, J=6.7),4.63 (1H, d, J=13.8), 7.60 (1H, dd, J=2.1, 8.8), 7.89-7.98 (4H, m), 8.48(1H, s).

Example 79((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(1,3-thiazol-2-yl)methanol

79a) tert-Butyl4-((2Z)-4-(hydroxy(1,3-thiazol-2-yl)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.10 g) as apale yellow solid was obtained from tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.47 g) obtained in Example 46a) and thiazole-2-carbaldehyde (0.26 g).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.52-1.87 (4H, m), 2.70 (2H, br), 2.91 (1H,m), 2.96 (3H, s), 3.06 (3H, s), 4.21 (2H, s), 6.09 (1H, s), 7.38 (1H, d,J=1.2), 7.78 (1H, d, J=1.2).

79b)((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(1,3-thiazol-2-yl)methanol

In the same manner as in Example 46b), the title compound (0.11 g) as apale yellow solid was obtained from the compound (0.10 g) obtained inExample 79a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.51-1.91 (5H, m), 2.51 (1H, m), 2.83-2.96 (5H, m),2.99-3.12 (5H, m), 3.50-3.60 (2H, m), 3.88 (1H, d, J=13.5), 6.07 (1H,s), 7.39 (1H, d, J=3.2), 7.59 (1H, dd, J=1.9, 8.7), 7.75 (1H, d, J=7.2),7.88-7.98 (4H, m), 8.48 (1H, s).

Example 80((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(3-methyl-1H-pyrazol-5-yl)methanol

80a) 5-Methyl-1-trityl-1H-pyrazole-3-carbaldehyde

To a solution of 5-methyl-1H-pyrazole-3-carbaldehyde (Werner A. et al.,Tetrahedron, 51, 4779 (1995): 1.1 g) in acetonitrile (20 mL),triethylamine (1.5 mL) and chlorotriphenylmethane (3.1 g) were added andmixed for 12 hours. The reaction solution was concentrated, and theresidue was dissolved in chloroform. This solution was washed with asaturated aqueous sodium bicarbonate solution and dried over anhydroussodium sulfate. The solvent was distilled off, and the residue waspurified with a silica gel column to give the title compound (1.9 g) asa colorless solid.

NMR (CDCl₃) δ: 1.54 (3H, s), 6.66 (1H, s), 7.09-7.17 (6H, m), 7.25-7.34(9H, m), 9.83 (1H, s).

80b) tert-Butyl4-((2Z)-4-(hydroxy(5-methyl-1-trityl-1H-pyrazol-3-yl)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.36 g) as acolorless solid was obtained from the compound (0.53 g) obtained inExample 80a) and tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.47 g) obtained in Example 46a).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.57-1.80 (4H, m), 2.65-2.78 (2H, m), 2.98(1H, m), 2.99 (3H, s), 3.28 (3H, s), 4.17 (2H, m), 5.80 (1H, s), 5.88(1H, s), 7.01-7.14 (6H, m), 7.26-7.30 (9H, m).

80c)((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(3-methyl-1H-pyrazol-5-yl)methanol

In the same manner as in Example 46b), the title compound (0.07 g) as apale yellow solid was obtained from the compound (0.36 g) obtained inExample 80a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.49-1.89 (4H, m), 2.29 (3H, d, J=3.8), 2.51 (1H, m),2.81-2.95 (2H, m), 2.96 (3H, s), 3.00-3.13 (5H, m), 3.49-3.62 (2H, m),3.89 (1H, m), 4.56 (1H, m), 5.79 (1H, J=7.4), 5.94 (1H, s), 7.60 (1H,dd, J=2.0, 8.8), 7.88-7.98 (4H, m), 8.48 (1H, s).

Example 81((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(2-thienyl)methanol

81a) tert-Butyl4-((2Z)-4-(hydroxy(2-thienyl)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.26 g) as acolorless solid was obtained from tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.62 g) obtained in Example 46a) and thiophene-2-carbaldehyde (0.28mL).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.50-1.85 (4H, m), 2.69 (2H, br), 2.93 (1H,m), 2.95 (3H, s), 3.11 (3H, s), 4.18 (2H, br), 6.12 (1H, s), 6.78 (1H,s), 6.95 (1H, m), 7.28 (1H, br).

81b)((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(2-thienyl)methanol

In the same manner as in Example 46b), the title compound (0.03 g) as apale yellow solid was obtained from the compound (0.25 g) obtained inExample 81a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.59-1.80 (4H, m), 2.51 (1H, m), 2.81-2.94 (2H, m), 2.97(3H, s), 3.00-3.15 (5H, m), 3.50-3.65 (2H, m), 3.90 (1H, m), 4.57 (1H,m), 6.14 (1H, s), 6.82 (1H, s), 6.98 (1H, m), 7.31 (1H, s), 7.60 (1H,dd, J=1.8, 8.8), 7.89-7.98 (4H, m), 8.48 (1H, s).

Example 82((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(3-thienyl)methanol

82a) tert-Butyl4-((2Z)-4-(hydroxy(3-thienyl)methyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.21 g) as acolorless solid was obtained from tert-butyl4-((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)piperidine-1-carboxylate(0.62 g) obtained in Example 46a) and thiophene-3-carbaldehyde (0.26mL).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.57-1.78 (4H, m), 2.70 (2H, m), 2.95 (1H,m), 2.96 (3H, s), 3.06 (3H, s), 4.18 (2H, br), 5.97 (1H, s), 6.90 (1H,m), 7.20 (1H, m), 7.31 (1H, m).

82b)((2Z)-5-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)(3-thienyl)methanol

In the same manner as in Example 46b), the title compound (0.02 g) as apale yellow solid was obtained from the compound (0.20 g) obtained inExample 82a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.59-1.72 (4H, m), 2.50 (1H, m), 2.85-2.94 (2H, m), 2.98(3H, s), 2.96-3.13 (5H, m), 3.50-3.62 (2H, m), 3.90 (1H, m), 4.62 (1H,m), 5.98 (1H, s), 6.92 (1H, br), 7.20 (1H, s), 7.33 (1H, m), 7.60 (1H,dd, J=1.8, 8.8), 7.89-7.98 (4H, m), 8.48 (1H, s).

Example 83N-((2Z)-3-(2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)ethyl)-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 57b), the title compound (0.27 g) wasobtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(2-iodoethyl)piperidine(0.52 g) obtained in Example 18c) and N-methyl-1,3-thiazol-2-amine (0.27g).

NMR (CDCl₃) δ: 1.00-1.18 (2H, m), 1.58-1.84 (5H, m), 2.48 (1H, t,J=12.9), 2.81-2.88 (2H, m), 2.98 (3H, s), 2.98 (1H, t, J=12.9),3.52-3.58 (2H, m), 3.79 (3H, m), 4.44 (1H, d, J=13.5), 5.96 (1H, d,J=5.1), 6.52 (1H, d, J=5.1), 7.57 (1H, dd, J=2.1, 7.8), 7.88-7.95 (4H,m), 8.46 (1H, s)

Example 84N-((2Z)-3-(2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)ethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

84a) N,5-Dimethyl-1,3-thiazol-2-amine

In the same manner as in Example 46a), the title compound (1.48 g) wasobtained from 2-bromopropionaldehyde (Pews R. et al., Synthetic Commun.,15, 977-84 (1985): 8.7 g) and N-methylthiourea (5.7 g).

NMR (CDCl₃) δ: 2.29 (3H, s), 2.95 (3H, s), 5.02 (1H, br), 6.75 (1H, s).

84b)N-((2Z)-3-(2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)ethyl)-5-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 57b), the title compound (0.24 g) wasobtained from the compound (0.26 g) obtained in Example 84a) and1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(2-iodoethyl)piperidine(0.52 g) obtained in Example 18c).

NMR (CDCl₃) δ: 1.00-1.16 (2H, m), 1.56-1.60 (3H, m), 1.70-1.84 (2H, m),2.13 (3H, s), 2.49 (1H, m), 2.81-2.89 (2H, m), 2.95 (3H, s), 2.96 (1H,m), 3.52-3.58 (2H, m), 3.68-3.80 (3H, m), 4.43 (1H, d, J=13.5), 6.18(1H, s), 7.59 (1H, dd, J=1.8, 8.3), 7.88-7.95 (4H, m), 8.45 (1H, s).

Example 85N-((2Z)-3-(2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)ethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

85a) N,4-Dimethyl-1,3-thiazol-2-amine

In the same manner as in Example 46a), the title compound (9.4 g) wasobtained from bromoacetone (25 g) and N-methylthiourea (20 g).

NMR (CDCl₃) δ: 2.23 (3H, s), 2.94 (3H, s), 6.04 (1H, s), 6.28 (1H, br).

85b)N-((2Z)-3-(2-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)ethyl)-4-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 57b), the title compound (0.06 g) wasobtained from the compound (0.26 g) obtained in Example 85a) and1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(2-iodoethyl)piperidine(0.52 g) obtained in Example 18c).

NMR (CDCl₃) δ: 1.06-1.14 (2H, m), 1.60-1.86 (5H, m), 2.08 (3H, s), 2.49(1H, t, J=12.3), 2.84-2.87 (2H, m), 2.95 (3H, s), 2.97 (1H, m),3.53-3.56 (2H, m), 3.70-3.81 (3H, m), 4.44 (1H, d, J=13.2), 5.51 (1H,s), 7.58 (1H, dd, J=1.8, 7.8), 7.88-7.95 (4H, m), 8.46 (1H, s).

Example 86N-((2Z)-3-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-1,3-thiazol-2(3H)-ylidene)-N-methylamine

86a)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-4-(iodomethyl)piperidine

In the same manner as in Example 46b), the title compound (4.0 g) wasobtained from tert-butyl 4-(iodomethyl)piperidine-1-carboxylate(Villalobos A. et al., J. Med. Chem., 37, 2721 (1994): 3.3 g) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (3. 0 g).

NMR (DMSO-d₆) δ: 0.65-0.89 (2H, m), 1.62-1.78 (3H, m), 2.40 (1H, m),2.67 (2H, t, J=7.8), 2.90 (1H, m), 3.15 (2H, d, J=6.2), 3.59 (2H, t,J=7.8), 3.76 (1H, d, J=14.0), 4.17 (1H, d, J=14.0), 7.72 (1H, dd, J=2.2,9.0), 7.97 (1H, dd, J=2.2, 8.8), 8.17 (1H, d, J=8.8), 8.19-8.25 (2H, m),8.63 (1H, s).

86b)N-((2Z)-3-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 57b), the title compound (0.06 g) wasobtained from the compound (0.50 g) obtained in Example 86a) andN-methyl-1,3-thiazol-2-amine (0.23 g).

NMR (CDCl₃) δ: 0.94-1.16 (2H, m), 1.63-1.77 (2H, m), 2.10 (1H, m), 2.49(1H, t, J=11.0), 2.84 (2H, dd, J=6.6, 10.4), 2.95 (3H, s), 2.99 (1H, t,J=11.0), 3.51-3.65 (4H, m), 3.81 (1H, d, J=13.4), 4.48 (1H, d, J=13.4),5.87 (1H, d, J=4.8), 6.41 (1H, d, J=4.8), 7.59 (1H, dd, J=1.8, 8.8),7.92-7.97 (4H, m), 8.47 (1H, s).

Example 873-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-1,3-thiazol-2(3H)-imine

In the same manner as in Example 57 b), the title compound (0.08 g) wasobtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-(iodomethyl)piperidine(0.50 g) obtained in Example 86a) and 1,3-thiazol-2-amine (0.20 g).

NMR (CDCl₃) δ: 0.98-1.28 (2H, m), 1.65-1.79 (2H, m), 2.10 (1H, m), 2.51(1H, t, J=13.2), 2.82-2.87 (2H, m), 3.00 (1H, t, J=13.2), 3.45-3.62 (4H,m), 3.83 (1H, d, J=13.8), 4.49 (1H, d, J=13.8), 5.74 (1H, d, J=4.8),6.29 (1H, d, J=4.8), 7.58 (1H, dd, J=1.8, 7.8), 7.88-7.95 (4H, m), 8.46(1H, s)

Example 881-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinamine

88a) tert-Butyl 4-thioureidopiperidine-1-carboxylate

In the same manner as in Example 66a), the title compound (2.8 g) as apale yellow solid was obtained from tert-butyl4-aminopiperidine-1-carboxylate (2.7 g).

NMR (CDCl₃) δ: 1.26-1.45 (2H, m), 1.45 (9H, s), 1.98-2.08 (2H, m), 2.90(2H, t, J=9.8), 3.98-4.10 (3H, m), 6.10 (2H, s), 6.74 (1H, d, J=7.2).

88b) tert-Butyl 4-(1,3-thiazol-2-yl)aminopiperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (0.88 g) as apale yellow solid was obtained from the compound (1.0 g) obtained inExample 88a) and chloroacetaldehyde (1.13 mL, a 40% aqueous solution).

NMR (CDCl₃) δ: 1.33-1.49 (2H, m), 1.46 (9H, s), 2.06 (2H, m), 2.92 (2H,m), 3.56 (1H, m), 4.02 (2H, bd, J=10.5), 4.95 (1H, br), 5.71 (1H, d,J=4.8), 6.72 (1H, d, J=4.8).

88c)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-(1,3-thiazol-2-yl)-4-piperidinamine

In the same manner as in Example 46b), the title compound (1.19 g) as apale yellow solid was obtained from the compound (0.88 g) obtained inExample 88b) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.86g).

NMR (DMSO-d₆) δ: 1.12-1.40 (2H, m), 1.82-1.94 (2H, m), 2.56 (1H, m),2.72-2.78 (3H, m), 3.10 (1H, m), 3.59-3.75 (2H, m), 3.99 (1H, d,J=14.1), 6.58 (1H, d, J=3.6), 6.98 (1H, d, J=3.6), 7.50 (1H, d, J=7.5),7.72 (1H, d, J=1.8, 8.1), 7.97 (1H, dd, J=1.8, 8.1), 8.17 (1H, d,J=8.1), 8.24-8.28 (2H, m), 8.63 (1H, s).

88d)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinamine

In the same manner as in Example 57b), the title compound (0.15 g) as acolorless solid was obtained from the compound (0.50 g) obtained inExample 88c) and methyl iodide (0.13 mL).

NMR (CDCl₃) δ: 1.58 (2H, m), 1.82 (2H, m), 2.88 (2H, t, J=6.6), 2.93(1H, m), 3.10-3.25 (5H, m), 3.56 (2H, t, J=6.6), 3.76 (1H, m), 4.05 (1H,m), 5.84 (1H, d, J=4.2), 6.44 (1H, d, J=4.2), 7.58 (1H, dd, J=1.8, 7.8),7.88-7.96 (4H, m), 8.47 (1H, s).

Example 891-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinamine

89a) tert-Butyl4-((4-methyl-1,3-thiazol-2-yl)amino)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (0.79 g) as apale yellow solid was obtained from tert-butyl4-thioureidopiperidine-1-carboxylate (0.69 g) obtained in Example 88a)and bromoacetone (0.34 mL).

NMR (CDCl₃) δ: 1.33-1.49 (2H, m), 1.46 (9H, s), 2.06 (2H, m), 2.22 (3H,s), 2.92 (2H, m), 3.56 (1H, m), 4.02 (2H, d, J=10.5), 4.95 (1H, br),6.07 (1H, s).

89b)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-(4-methyl-1,3-thiazol-2-yl)-4-piperidinamine

In the same manner as in Example 47b), the title compound (0.76 g) as apale yellow solid was obtained from the compound (0.79 g) obtained inExample 89a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.80g).

NMR (CDCl₃) δ: 1.25-1.46 (2H, m), 2.06-2.21 (2H, m), 2.22 (3H, s),2.80-2.91 (3H, m), 3.20 (1H, m), 3.53-3.68 (3H, m), 3.79 (1H, d, J=9.4),4.32 (1H, d, J=9.4), 4.87 (1H, d, J=4.8), 6.05 (1H, s), 7.58 (1H, dd,J=1.4, 9.0), 7.88-7.95 (4H, m), 8.46 (1H, s).

89c)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinamine

In the same manner as in Example 57b), the title compound (0.42 g) as apale yellow solid was obtained from the compound (0.65 g) obtained inExample 89b) and methyl iodide (0.17 mL).

NMR (CDCl₃) δ: 1.38-1.64 (2H, m), 1.88-2.01 (2H, m), 2.36 (3H, s), 2.66(2H, t, J=8.1), 2.92 (2H, m), 3.15 (1H, m), 3.46 (3H, s), 3.57 (2H, m),3.93 (1H, brd, J=14.4), 4.57 (1H, brd, J=14.4), 6.61 (1H, s), 7.60 (1H,dd, J=1.8, 7.8), 7.90-7.97 (4H, m), 8.48 (1H, s).

Example 901-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinamine

90a) tert-Butyl4-((5-methyl-1,3-thiazol-2-yl)amino)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (2.0 g) as apale yellow solid was obtained from tert-butyl4-thioureidopiperidine-1-carboxylate (5.2 g) obtained in Example 88a)and 2-bromopropionaldehyde (2.8 g).

NMR (CDCl₃) δ: 1.33-1.49 (2H, m), 1.46 (9H, s), 2.06 (2H, m), 2.28 (3H,s), 2.92 (2H, m), 3.56 (1H, m), 4.02 (2H, brd, J=10.5), 4.95 (1H, br),5.71 (1H, s).

90b)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-(5-methyl-1,3-thiazol-2-yl)-4-piperidinamine

In the same manner as in Example 46b), the title compound (2.84 g) as apale yellow solid was obtained from the compound (1.8 g) obtained inExample 90a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (1.77g).

NMR (CDCl₃) δ: 1.25-1.47 (2H, m), 2.03-2.21 (2H, m), 2.28 (3H, s),2.77-2.91 (3H, m), 3.19 (1H, m), 3.54 (2H, m), 3.69 (1H, br), 3.80 (1H,d, J=13.2), 4.34 (1H, d, J=13.2), 4.87 (1H, br), 6.71 (1H, s), 7.60 (1H,dd, J=1.8, 8.7), 7.88-7.95 (4H, m), 8.46 (1H, s).

90c)1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3,5-dimethyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinamine

In the same manner as in Example 57b), the title compound (0.43 g) as apale yellow solid was obtained from the compound (0.80 g) obtained inExample 90b) and methyl iodide (0.42 mL).

NMR (CDCl₃) δ: 1.40-1.88 (4H, m), 2.10 (3H, s), 2.88 (2H, dd, J=6.8,9.0), 2.96-3.12 (2H, m), 3.15-3.27 (4H, m), 3.51-3.65 (2H, m), 3.76 (1H,m), 4.10 (1H, m), 6.13 (1H, s), 7.59 (1H, dd, J=2.0, 8.8), 7.89-7.98(4H, m), 8.48 (1H, s).

Example 912-((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-1,3-thiazol-3(2H)-yl)acetamide

In the same manner as in Example 57b), the title compound (0.61 g) as apale yellow solid was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-N-(1,3-thiazol-2-yl)-4-piperidinamine(0.50 g) obtained in Example 88c) and iodoacetamide (0.40 g).

NMR (CDCl₃) δ: 1.39-1.62 (2H, m), 1.72-1.90 (2H, m), 2.89 (2H, t,J=7.2), 3.06. (1H, m), 3.15-3.33 (2H, m), 3.57 (2H, t, J=7.2), 3.71 (1H,m), 3.97 (1H, m), 4.31 (2H, s), 5.54 (1H, br), 5.98 (1H, d, J=4.6), 6.58(1H, d, J=4.6), 7.08 (1H, br), 7.60 (1H, dd, J=2.2, 9.2), 7.88-7.98 (4H,m), 8.49 (1H, s).

Example 922-((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-1,3-thiazol-3(2H)-yl)ethanol

To a solution of the compound (0.60 g) obtained in Example 88c) in DMF(2.0 mL), 2-iodoethanol (0.2 mL) was added, and the mixture was mixed at80° C. for 2 hours. The reaction solution was concentrated under reducedpressure. Chloroform and a saturated aqueous sodium hydrogen carbonatesolution were added to the residue, and the mixture was mixed for 15minutes. The organic layer was collected by separation, dried overanhydrous sodium sulfate, and the solvent was distilled off underreduced pressure. The residue was purified with a silica gel column togive the title compound (0.25 g) as a white solid.

NMR (CDCl₃) δ: 1.41-1.62 (2H, m), 1.72-1.87 (2H, m), 2.79-2.90 (2H, m),3.03 (1H, m), 3.23-3.33 (2H, m), 3.53-3.59 (2H, m), 3.64-3.72 (1H, m),3.85-3.91 (5H, m), 5.90 (1H, d, J=5.1), 6.59 (1H, d, J=5.1), 7.58 (1H,dd, J=1.8, 7.8), 7.89-7.95 (4H, m), 8.47 (1H, s).

Example 931-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3-(2-methoxyethyl)-1,3-thiazol-2(3H)-ylidene)-4-piperidinamine

In the same manner as in Example 57b), the title compound (0.21 g) as awhite solid was obtained from the compound (0.47 g) obtained in Example88c), 1-bromo-2-methoxyethane (0.19 mL) and potassium iodide (0.33 g).

NMR (CDCl₃) δ: 1.53-1.85 (4H, m), 2.82-2.94 (2H, m), 3.01 (1H, m),3.21-3.35 (2H, m), 3.34 (3H, s), 3.52-3.66 (4H, m), 3.73 (1H, m), 3.86(2H, t, J=4.8), 3.95 (1H, m), 5.81 (1H, d, J=4.7), 6.58 (1H, d, J=4.7)7.59 (1H, dd, J=2.0, 8.8), 7.89-7.98 (4H, m), 8.48 (1H, s).

Example 94((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-5-methyl-1,3-thiazol-3(2H)-yl)aceticacid hydrochloride

94a) tert-Butyl((2Z)-2-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-5-methyl-1,3-thiazol-3(2H)-yl)acetate

In the same manner as in Example 57b), the title compound (0.68 g) as awhite solid was obtained from1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-N-(5-methyl-1,3-thiazol-2-yl)-4-piperidinamine(0.90 g) obtained in Example 90b), t-butyl bromoacetate (1.01 mL) andpotassium iodide (0.63 g).

NMR (CDCl₃) δ: 1.44 (9H, s), 1.46-1.72 (4H, m), 2.09 (3H, s), 2.87 (2H,t, J=7.8), 3.01 (1H, m), 3.29 (2H, m), 3.54 (2H, t, J=7.8), 3.67 (1H,m), 3.84 (1H, m), 4.21 (2H, s), 6.13 (1H, s), 7.58 (1H, dd, J=1.8, 8.7),7.89-8.00 (4H, m), 8.47 (1H, s).

94b)((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-5-methyl-1,3-thiazol-3(2H)-yl)aceticacid hydrochloride

To a solution of the compound (0.40 g) obtained in Example 94a) in THF(10 mL), concentrated hydrochloric acid (5 mL) was added, and themixture was mixed for 12 hours. The reaction solution was concentrated,and the residue was washed with diethyl ether to give the title compound(0.38 g) as a colorless solid.

NMR (DMSO-d₆) δ: 1.45 (1H, m), 1.60 (1H, m), 1.83-1.98 (2H, m), 2.28(3H, s), 2.64 (1H, m), 2.68-2.83 (2H, m), 3.14 (1H, m), 3.57-3.69 (3H,m), 3.88 (1H, d, J=14.5), 4.22 (1H, d, J=14.5), 5.01 (2H, s), 7.24 (1H,s), 7.74 (1H, dd, J=2.2, 8.8), 8.00 (1H, dd, J=1.9, 8.8), 8.17-8.31 (3H,m), 8.65 (1H, d, J=1.9), 10.00 (1H, br).

Example 951-((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-5-yl)ethanol

95a) tert-Butyl4-(((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)piperidine-1-carboxylate

In the same manner as in Example 57b), the title compound (4.2 g) as apale yellow solid was obtained from tert-butyl4-(1,3-thiazol-2-ylamino)piperidine-1-carboxylate (5.0 g) obtained inExample 88b) and methyl iodide (2.18 mL).

NMR (CDCl₃) δ: 1.46 (9H, s), 1.51-1.85 (4H, m), 2.82-3.08 (3H, m), 3.26(3H, s), 3.96 (2H, br), 5.83 (1H, d, J=4.8), 6.45 (1H, d, J=4.8).

95b) tert-Butyl4-((2Z)-5-(1-hydroxyethyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (0.18 g) wasobtained from the compound (1.0 g) obtained in Example 95a) andacetaldehyde (0.5 mL).

NMR (CDCl₃) δ: 1.46 (9H, s), 1.47 (3H, d, J=6.3), 1.50-1.59 (2H, m),1.67-1.78 (2H, m), 2.86-3.02 (2H, m), 3.21 (3H, s), 3.96 (2H, br), 4.75(1H, q, J=6.3), 6.36 (1H, s).

95c)1-((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-5-yl)ethanol

To the compound (0.18 g) obtained in Example 95b), concentratedhydrochloric acid (2 mL) was added, and the mixture was mixed. Aftercompletion of expansion, ethanol was added thereto, and the mixture wasconcentrated. To the residue, DBU (0.16 mL), triethylamine (0.15 mL) andN-trimethylsilylacetamide (0.28 g) were added, and the mixture wasdissolved in acetonitrile (5 mL). This solution was added to asuspension of 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.16 g),WSC (0.15 g) and HOBt (0.12 g) in acetonitrile (5 mL) and mixed for 12hours. The reaction solution was concentrated, and the residue wasdissolved in chloroform and a saturated aqueous sodium bicarbonatesolution. The organic layer was collected by separation, and dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas purified with a silica gel column to give the title compound (0.07g) as a colorless solid.

NMR (CDCl₃) δ : 1.46 (3H, d, J=6.2), 1.48-1.80 (4H, m), 2.88 (2H, t,J=7.8), 2.92-3.29 (3H, m), 3.21 (3H, s), 3.56 (2H, t, J=7.8), 3.81 (1H,m), 4.10 (1H, m), 4.75 (1H, q, J=6.2), 6.38 (1H, s), 7.59 (1H, dd,J=1.8, 9.0), 7.88-7.97 (4H, m), 8.48 (1H, s).

Example 96((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-5-yl)methanol

96a) tert-Butyl4-(((2Z)-5-formyl-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)piperidine-1-carboxylate

In the same manner as in Example 67a), the title compound (4.6 g) as apale yellow solid was obtained from the compound (5.0 g) obtained inExample 95a) and DMF (4 mL).

NMR (CDCl₃) δ: 1.47 (9H, s), 1.27-1.81 (4H, m), 2.97-3.14 (3H, m), 3.41(3H, s), 3.91 (2H, br), 7.43 (1H, s), 9.46 (1H, s).

96b) tert-Butyl4-(((2Z)-5-(hydroxymethyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)piperidine-1-carboxylate

To a solution of the compound (1.0 g) obtained in Example 96a) inethanol (10 mL), sodium borohydride (0.23 g) was added, and the mixturewas mixed for 30 minutes. The reaction solution was concentrated, andthe residue was purified with a silica gel column to give the titlecompound (0.98 g) as a colorless solid.

NMR (CDCl₃) δ: 1.46 (9H, s), 1.48-1.59 (2H, m), 1.69-1.80 (2H, m),2.86-3.02 (3H, m), 3.22 (3H, s), 3.94 (2H, br), 4.45 (2H, s), 6.42 (1H,s).

96c)((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-5-yl)methanol

In the same manner as in Example 95c), the title compound (0.33 g) as acolorless solid was obtained from the compound (0.98 g) obtained inExample 96b) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.91g).

NMR (DMSO-d₆) δ: 1.18 (1H, m), 1.36 (1H, m), 1.56 (1H, m), 1.66 (1H, m),2.65-2.79 (2H, m), 2.82-2.97 (2H, m), 3.11 (3H, s), 3.18 (1H, m),3.59-3.72 (3H, m), 3.86 (1H, m), 4.23 (2H, d, J=5.3), 5.10 (1H, t,J=5.6), 6.77 (1H, s), 7.73 (1H, dd, J=2.2, 8.8), 7.99 (1H, dd, J=1.7,8.8), 8.23-8.32 (2H, m), 8.65 (1H, s).

Example 97 Ethyl(2Z)-2-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-4-carboxylate

97a) tert-Butyl4-((4-(ethoxycarbonyl)-1,3-thiazol-2-yl)amino)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (0.41 g) wasobtained from tert-butyl 4-thioureidopiperidine-1-carboxylate (3.0 g)obtained in Example 88a) and ethyl bromopyruvate (2.18 mL).

NMR (CDCl₃) δ: 1.37 (3H, t, J=6.9), 1.46 (9H, s), 1.39-1.47 (2H, m),2.04-2.09 (2H, m), 2.96 (2H, m), 3.53 (1H, m), 4.00 (2H, brd, J=12.0),4.35 (2H, q, J=6.9), 5.22 (1H, d, J=8.4), 7.41 (1H, s).

97b) Ethyl2-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)amino)-1,3-thiazol-4-carboxylate

In the same manner as in Example 46b), the title compound (0.44 g) as acolorless solid was obtained from the compound (0.46 g) obtained inExample 97a) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.39g).

NMR (CDCl₃) δ: 1.29-1.50 (5H, m), 2.05-2.20 (2H, m), 2.81-2.91 (2H, m),3.22 (1H, m), 3.53-3.58 (2H, m), 3.68 (1H, m), 3.81 (1H, d, J=14.4),4.31-4.36 (3H, m), 5.17 (1H, d, J=8.1), 7.41 (1H, s), 7.59 (1H, dd,J=2.1, 8.7), 7.88-7.96 (4H, m), 8.46 (1H, s).

97c) Ethyl(2Z)-2-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-4-carboxylate

In the same manner as in Example 57b), the title compound (0.21 g) wasobtained from the compound (0.44 g) obtained in Example 97b) and methyliodide (0.12 mL).

NMR (CDCl₃) δ: 1.35 (3H, t, J=7.2), 1.47-1.81 (4H, m), 2.84-2.96 (2H,m), 3.08 (1H, m), 3.19-3.33 (2H, m), 3.54 (3H, s), 3.51-3.60 (2H, m),3.77 (1H, m), 3.97 (1H, m), 4.29 (2H, q, J=7.2), 6.91 (1H, s), 7.59 (1H,dd, J=1.8, 8.8), 7.90-8.01 (4H, m), 8.48 (1H, s).

Example 98(2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-N,3,4-trimethyl-2,3-dihydro-1,3-thiazole-5-carboxamide

98a) tert-Butyl4-((4-methyl-5-(methylcarbamoyl)-1,3-thiazol-2-yl)amino)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (1.4 g) wasobtained from tert-butyl 4-thioureidopiperidine-1-carboxylate (1.5 g)obtained in Example 88a) and 2-chloro-N-methyl-3-oxobutanamide (1.0 g).

NMR (CDCl₃) δ: 1.39-1.49 (2H, m), 1.46 (9H, s), 2.03-2.10 (2H, m), 2.49(3H, s), 2.81-2.95 (5H, m), 3.51 (1H, m), 4.03 (2H, brd, J=12.8), 5.32(1H, d, J=6.6), 5.48 (1H, br).

98b)2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)amino)-N,4-dimethyl-1,3-thiazole-5-carboxamide

In the same manner as in Example 46b), the title compound (1.8 g) wasobtained from the compound (1.4 g) obtained in Example 98a) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (1.2 g).

NMR (CDCl₃) δ: 1.30-1.49 (2H, m), 2.01-2.19 (2H, m), 2.48 (3H, s),2.77-2.94 (3H, m), 2.93 (3H, d, J=4.8), 3.19 (1H, t, J=14.1), 3.52-3.61(2H, m), 3.69 (1H, m), 3.81 (1H, d, J=14.1), 4.37 (1H, d, J=14.1), 5.51(1H, d, J=7.2), 5.55 (1H, d, J=4.8), 7.59 (1H, dd, J=1.8, 7.8),7.88-7.97 (4H, m), 8.47 (1H, s).

98c)(2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-N,3,4-trimethyl-2,3-dihydro-1,3-thiazole-5-carboxamide

In the same manner as in Example 57b), the title compound (0.48 g) wasobtained from the compound (0.8 g) obtained in Example 98b) and methyliodide (0.25 mL).

NMR (DMSO-d₆) δ: 1.18 (1H, m), 1.41 (1H, m), 1.58 (1H, m), 1.70 (1H, m),2.44 (3H, s), 2.63 (3H, d, J=4.5), 2.68-2.79 (2H, m), 2.86-3.00 (2H, m),3.17 (1H, m), 3.21 (3H, s), 3.59-3.73 (3H, m), 3.86 (1H, s, J=13.0),7.45 (1H, m), 7.73 (1H, dd, J=2.2, 8.8), 7.98 (1H, m), 8.17 (1H, d,J=8.8), 8.24-8.32 (2H, m), 8.65 (1H, d, J=1.5).

Example 99((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)methanol

99a)tert-Butyl-4-((4-((acetyloxy)methyl)-1,3-thiazol-2-yl)amino)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (3.5 g) wasobtained from tert-butyl 4-thioureidopiperidine-1-carboxylate (7.2 g)obtained in Example 88a) and 3-bromo-2-oxopropyl acetate (5.0 g).

NMR (CDCl₃) δ: 1.39-1.48 (2H, m), 1.46 (9H, s), 2.05-2.11 (2H, m), 2.95(2H, t, J=7.8), 3.53 (1H, m), 4.02 (2H, br), 4.95 (2H, s), 5.04 (1H, d,J=5.2), 6.47 (1H, s).

99b) tert-Butyl4-((4-(hydroxymethyl)-1,3-thiazol-2-yl)amino)piperidine-1-carboxylate

In the same manner as in Example 57b), the title compound (0.92 g) wasobtained from the compound (1.0 g) obtained in Example 99a) and methyliodide (0.35 mL).

NMR (CDCl₃) δ: 1.46 (9H, s), 1.50-1.61 (2H, m), 1.73-1.83 (2H, m),2.91-3.05 (3H, m), 3.32 (3H, s), 3.94 (2H, br), 4.39 (2H, d, J=5.7),5.82 (1H, s).

99c)((2Z)-2-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)imino)-3-methyl-2,3-dihydro-1,3-thiazol-4-yl)methanol

In the same manner as in Example 95c), the title compound (0.13 g) wasobtained from the compound (0.33 g) obtained in Example 99b) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (0.27 g).

NMR (CDCl₃) δ: 1.46-1.88 (4H, m), 2.88 (2H, t, J=6.9), 3.04 (1H, m),3.10-3.30 (2H, m), 3.32 (3H, s), 3.55 (2H, t, J=6.9), 3.76 (1H, m), 4.05(1H, m), 4.40 (2H, s), 5.83 (1H, s), 7.58 (1H, dd, J=1.8, 8.4),7.89-7.96 (4H, m), 8.47 (1H, s).

Example 100N-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amine

100a) tert-Butyl 4-((thioureido)methyl)piperidine-1-carboxylate

In the same manner as in Example 66a), the title compound (9.0 g) wasobtained from tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (10 g)and benzoyl isothiocyanate (6.3 mL).

NMR (CDCl₃) δ: 1.07-1.23 (2H, m), 1.45 (9H, s), 1.65-1.89 (3H, m),2.62-2.77 (2H, m), 4.03-4.17 (2H, m), 6.03-6.18 (2H, br).

100b) tert-Butyl4-((1,3-thiazol-2-yl)aminomethyl)piperidine-1-carboxylate

In the same manner as in Example 46a), the title compound (1.4 g) wasobtained from the compound (3.0 g) obtained in Example 100a) andchloroacetaldehyde (3.3 mL, a 40% aqueous solution).

NMR (CDCl₃) δ: 1.12-1.27 (2H, m) 1.45 (9H, s), 1.73-1.86 (3H, m), 2.69(2H, m), 3.18 (2H, d, J=6.6), 4.11 (2H, m), 5.73 (1H, br), 6.47 (1H, d,J=3.6), 7.09 (1H, d, J=3.6).

100c)N-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-1,3-thiazol-2-amine

In the same manner as in Example 46b), the title compound (1.72 g) wasobtained from the compound (1.26 g) obtained in Example 100b) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (1.27 g).

NMR (CDCl₃) δ: 1.05-1.23 (2H, m), 1.76-1.95 (3H, m), 2.51 (1H, m), 2.85(2H, m), 2.97 (1H, m), 3.19 (2H, d, J=3.9), 3.54 (2H, m), 3.85 (1H, d,J=13.8), 4.51 (1H, d, J=13.8), 5.44 (1H, br), 6.48 (1H, d, J=3.6), 7.09(1H, d, J=3.6), 7.59 (1H, dd, J=1.8, 8.7), 7.88 (4H, m), 8.46 (1H, s).

100d)N-((1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)methyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amine

In the same manner as in Example 57b), the title compound (0.31 g) wasobtained from the compound (0.80 g) obtained in Example 100c) and methyliodide (0.42 mL).

NMR (CDCl₃) δ: 1.06-1.22 (2H, m), 1.73-1.82 (3H, m), 2.53 (1H, m),2.82-2.96 (4H, m), 3.02 (1H, m), 3.27 (3H, s), 3.49-3.62 (2H, m), 3.87(1H, d, J=13.5), 4.47 (1H, d, J=13.5), 5.85 (1H, d, J=4.9), 6.48 (1H, d,J=4.9), 7.59 (1H, dd, J=1.9, 8.6), 7.89-8.01 (4H, m), 8.47 (1H, s).

Example 1016-Chloro-N-(2-(4-(((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)-1-piperidinyl)-2-oxoethyl)-2-naphthalenesulfonamide

101a)6-Chloro-N-(2-oxo-2-(4-(1,3-thiazol-2-ylamino)-1-piperidinyl)ethyl)-2-naphthalenesulfonamide

In the same manner as in Example 46b), the title compound (0.7 g) wasobtained from tert-butyl4-(1,3-thiazol-2-yl)aminopiperidine-1-carboxylate (0.57 g) obtained inExample 88b) and N-((6-chloro-2-naphthyl)sulfonyl)glycine (0.6 g).

NMR (CDCl₃) δ: 1.14-1.42 (2H, m), 1.78-1.96 (2H, m), 2.75 (1H, t,J=11.0), 3.00-3.12 (2H, m), 3.62-4.01 (4H, m), 6.59 (1H, d, J=3.6), 6.98(1H, d, J=3.6), 7.53 (1H, d, J=7.0), 7.68 (1H, dd, J=2.2, 7.0),7.86-7.94 (2H, m), 8.10-8.23 (2H, m), 8.49 (1H, s).

101b)6-Chloro-N-(2-(4-(((-2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)-1-piperidinyl)-2-oxoethyl)-2-naphthalenesulfonamide

In the same manner as in Example 57b), the title compound (0.29 g) wasobtained from the compound (0.7 g) obtained in Example 101a) and methyliodide (0.19 mL).

NMR (DMSO-d₆) δ: 1.20 (1H, m), 1.39 (1H, m), 1.55-1.72 (2H, m),2.80-2.92 (2H, m), 3.13 (1H, m), 3.13 (3H, s), 3.61 (1H, m), 3.78-3.90(3H, m), 6.18 (1H, br), 6.91 (1H, br), 7.68 (1H, dd, J=2.2, 8.8), 7.84(1H, t, J=5.6), 7.92 (1H, dd, J=1.9, 8.8), 8.10 (1H, d, J=8.0),8.17-8.24 (2H, m), 8.49 (1H, s).

Example 1022-(((6-Chloro-2-naphthyl)sulfonyl)(2-(4-(((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)-1-piperidinyl)-2-oxoethyl)amino)acetamide

102a)2-(((6-Chloro-2-naphthyl)sulfonyl)(2-oxo-2-(4-(1,3-thiazol-2-ylamino)-1-piperidinyl)ethyl)amino)acetamide

In the same manner as in Example 46b), the title compound (0.62 g) wasobtained from tert-butyl4-(1,3-thiazol-2-yl)aminopiperidine-1-carboxylate (0.57 g) obtained inExample 88b) andN-(2-amino-2-oxoethyl)-N-((6-chloro-2-naphthyl)sulfonyl)glycine (0.71g).

NMR (CDCl₃) δ: 1.21-1.42 (2H, m), 1.89-2.05 (2H, m), 2.86 (1H, m), 3.16(1H, m), 3.72-3.82 (4H, m), 4.10 (1H, m), 4.36 (1H, d, J=2.8), 6.61 (1H,d, J=3.6), 7.00 (1H, d, J=3.6), 7.16 (1H, br), 7.58 (1H, s, J=6.8), 7.70(1H, dd, J=1.8, 8.8), 7.93 (1H, dd, J=1.8, 8.8), 8.02 (1H, br), 8.10(1H, d, J=8.8), 8.20-8.25 (2H, m), 8.55 (1H, s)

102b)2-(((6-Chloro-2-naphthyl)sulfonyl)(2-(4-(((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)-1-piperidinyl)-2-oxoethyl)amino)acetamide

In the same manner as in Example 57b), the title compound (0.27 g) wasobtained from the compound (0.62 g) obtained in Example 102a) and methyliodide (0.15 mL).

NMR (DMSO-d₆) δ: 1.28-1.58 (2H, m), 1.68-1.84 (2H, m), 2.93-3.08 (2H,m), 3.15-3.30 (4H, m), 3.30 (3H, s), 3.75 (1H, m), 3.83 (2H, s), 4.03(1H, m), 4.36 (2H, s), 7.14 (1H, s), 7.70 (1H, dd, J=2.0, 9.0), 7.94(1H, dd, J=1.9, 8.8), 8.11 (1H, d, J=8.8), 8.19-8.27 (2H, m), 8.56 (1H,s).

Example 1031-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinaminedihydrochloride

103a) tert-Butyl5-chloro-2-((3-oxo-3-(4-(1,3-thiazol-2-ylamino)-1-piperidinyl)propyl)sulfonyl)-1H-indole-1-carboxylate

In the same manner as in Example 46b), the title compound (0.64 g) wasobtained from tert-butyl4-(1,3-thiazol-2-ylamino)piperidine-1-carboxylate (0.57 g) obtained inExample 88b) and3-((1-tert-butoxycarbonyl)-5-chloro-1H-indol-2-yl)sulfonylpropanoic acid(0.77 g).

NMR (CDCl₃) δ: 1.39-1.64 (2H, m), 1.74 (9H, s), 2.03-2.20 (2H, m),2.90-3.03 (3H, m), 3.25 (1H, m), 3.62 (1H, m), 3.84 (1H, d, J=14.2),3.95-4.10 (2H, m), 4.29 (1H, d, J=14.2), 6.49 (1H, d, J=3.6), 7.08 (1H,d, J=3.6), 7.37-7.52 (2H, m), 7.66 (1H, m), 8.00 (1H, d, J=8.8).

103b) tert-Butyl5-chloro-2-((3-(4-(((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)amino)-1-piperidinyl)-3-oxopropyl)sulfonyl)-1H-indole-1-carboxylate

In the same manner as in Example 57b), the title compound (0.32 g) wasobtained from the compound (0.64 g) obtained in Example 103a) and methyliodide (0.14 mL).

NMR (CDCl₃) δ: 1.45-1.64 (2H, m), 1.64 (9H, s), 1.75-1.87 (2H, m), 2.90(2H, t, J=6.6), 2.99 (1H, m), 3.04-3.31 (2H, m), 3.25 (3H, s), 3.68 (2H,t, J=6.6), 3.78 (1H, m), 4.08 (1H, m), 5.84 (1H, d, J=4.8), 6.45 (1H, d,J=4.8), 7.13 (1H, s), 7.31 (1H, dd, J=1.8, 8.7), 7.40 (1H, d, J=8.7),7.68 (1H, d, J=1.8).

103c)1-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)-4-piperidinaminedihydrochloride

In the same manner as in Example 52b), the title compound (0.30 g) wasobtained from the compound (0.32 g) obtained in Example 103b).

NMR (DMSO-d₆) δ: 1.48 (1H, m), 1.69 (1H, m), 1.86-2.01 (2H, m), 2.63(1H, m), 2.68-2.82 (2H, m), 3.12 (1H, m), 3.40-3.50 (1H, m), 3.67 (5H,s), 3.87 (1H, d, J=13.5), 4.25 (1H, d, J=13.5), 7.10-7.18 (2H, m), 7.34(1H, dd, J=2.1, 8.6), 7.48-7.61 (2H, m), 7.80-7.91 (1H, m), 9.70 (1H, d,J=7.7), 12.63 (1H, s).

Example 104N-((2Z)-5-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

104a) N-((2Z)-3,4-Dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

In the same manner as in Example 57b), the title compound (2.8 g) as abrownish-red viscous oily matter was obtained frommethyl(4-methyl-1,3-thiazol-2-yl)amine (8.0 g) obtained in Example 85a)and methyl iodide (7.8 mL).

NMR (CDCl₃) δ: 2.08 (3H, s), 2.99 (3H, s), 3.23 (3H, s), 5.53 (1H, s).

104b)(2Z)-3,4-Dimethyl-2-(methylimino)-2,3-dihydro-1,3-thiazole-5-carbaldehyde

In the same manner as in Example 67a), the title compound (0.76 g) wasobtained from the compound (1.0 g) obtained in Example 104a) and DMF(1.0 mL).

NMR (CDCl₃) δ: 2.49 (3H, s), 3.06 (3H, s), 3.38 (3H, s), 9.71 (1H, s).

104c)N-((2Z)-5-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine

To a solution of the compound (0.34 g) obtained in Example 104b) and1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)piperazine (0.73 g)obtained in Example 3a) in 1,2-dichloroethane (10 mL), acetic acid (0.14mL) and sodium triacetoxyborohydride (0.64 g) were added and mixed for12 hours. The reaction solution was diluted with chloroform, washed witha saturated aqueous sodium bicarbonate solution, and dried overanhydrous sodium sulfate. The solvent was distilled off, and the residuewas purified with a silica gel column to give the title compound (0.76g).

NMR (CDCl₃) δ: 2.04 (3H, s), 2.36 (2H, t, J=5.0), 2.44 (2H, t, J=5.0),2.87 (2H, dd, J=7.0, 8.0), 3.00 (3H, s), 3.25 (3H, s), 3.35 (2H, s),3.46 (2H, t, J=5.0), 3.50-3.60 (4H, m), 7.60 (1H, dd, J=1.8, 8.8),7.92-7.98 (4H, m), 8.48 (1H, s).

Example 1052-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole

105a) 3-Methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole

In the same manner as in Example 46a), the title compound (15.0 g) wasobtained from bromoacetone (25.0 g) and ethylene thiourea (12.4 g).

NMR (CDCl₃) δ: 2.11 (3H, s), 4.27-4.38 (4H, m), 6.55 (1H, s).

105b) 3-Methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole-2-carbaldehyde

In the same manner as in Example 67a), the title compound (1.17 g) wasobtained from the compound (1.0 g) obtained in Example 105a) and DMF(1.0 mL).

NMR (CDCl₃) δ: 2.40 (3H, s), 3.90 (2H, dd, J=8.0, 9.6), 4.35 (2H, dd,J=8.0, 9.6), 9.57 (1H, s).

105c)2-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-5,6-dihydroimidazo[2,1-b][1,3]thiazole

In the same manner as in Example 104c), the title compound (0.34 g) wasobtained from the compound (0.34 g) obtained in Example 105b).

NMR (CDCl₃) δ: 2.07 (3H, s), 2.33-2.49 (4H, m), 2.80-2.94 (2H, m), 3.33(2H, s), 3.43-3.59 (6H, m), 4.04 (2H, t, J=9.4), 4.30 (2H, t, J=9.4),7.60 (1H, dd, J=1.8, 8.8), 7.88-7.98 (4H, m), 8.47 (1H, s).

Example 1062-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine

106a) 3-Methyl-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine

In the same manner as in Example 46a), the title compound (17.9 g) wasobtained from bromoacetone (25.0 g) and propylene thiourea (15.0 g).

NMR (CDCl₃) δ: 1.84-1.96 (2H, m), 1.99 (3H, s), 3.45 (2H, t, J=5.8),3.66 (2H, t, J=5.8), 5.33 (1H, m).

106b)3-Methyl-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-2-carbaldehyde

In the same manner as in Example 67a), the title compound (5.84 g) wasobtained from the compound (7.0 g) obtained in Example 106a) and DMF(7.0 mL).

NMR (CDCl₃) δ: 1.98 (2H, dt, J=5.6, 6.0), 2.37 (3H, s), 3.53 (2H, t,J=5.6), 3.78 (2H, t, J=6.0), 9.71 (1H, s).

106c)2-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-6,7-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine

In the same manner as in Example 104c), the title compound (0.51 g) wasobtained from the compound (0.55 g) obtained in Example 106b).

NMR (CDCl₃) δ: 2.05 (3H, s), 2.35 (2H, t, J=5.1), 2.44 (2H, t, J=5.1),2.85 (2H, t, J=8.1), 3.34 (2H, s), 3.44 (2H, t, J=5.1), 3.49-3.58 (8H,m), 3.77 (2H, t, J=5.1), 7.59 (1H, dd, J=2.1, 8.7), 7.88-7.96 (4H, m),8.46 (1H, s).

Example 107N-((2Z)-5-((4-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminedihydrochloride

107a) tert-Butyl4-(((2Z)-3,4-dimethyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)-1-piperazinecarboxylate

In the same manner as in Example 104c), the title compound (0.64 g) as acolorless solid was obtained from(2Z)-3,4-dimethyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-carbaldehyde(0.41 g) obtained in Example 104b) and tert-butylpiperazine-1-carboxylate (0.45 g).

NMR (CDCl₃) δ: 1.46 (9H, s), 2.04 (3H, s), 2.39 (4H, t, J=5.1), 2.99(3H, s), 3.24 (3H, s), 3.35 (2H, s), 3.43 (4H, t, J=5.1).

107b) tert-Butyl5-chloro-2-((3-(4-(((2Z)-3,4-dimethyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-5-yl)methyl)-1-piperazinyl)-3-oxopropyl)sulfonyl)-1H-indole-1-carboxylate

In the same manner as in Example 46b), the title compound (0.40 g) wasobtained from the compound (0.34 g) obtained in Example 107c) and3-((1-tert-butoxycarbonyl)-5-chloro-1H-indol-2-yl)sulfonylpropanoic acid(0.39 g).

NMR (CDCl₃) δ: 1.73 (9H, s), 2.05 (3H, s), 2.32-2.46 (4H, m), 2.91 (2H,t, J=7.6), 3.00 (3H, s), 3.24 (3H, s), 3.35 (2H, s), 3.44-3.58 (4H, m),4.04 (2H, t, J=7.6), 7.44 (1H, dd, J=2.2, 9.0), 7.51 (1H, s), 7.65 (1H,d, J=2.2), 8.00 (1H, d, J=9.0). 107c)N-((2Z)-5-((4-(3-((5-Chloro-1H-indol-2-yl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3,4-dimethyl-1,3-thiazol-2(3H)-ylidene)-N-methylaminedihydrochloride

In the same manner as in Example 7b), the title compound (0.38 g) wasobtained from the compound (0.40 g) obtained in Example 107a).

NMR (DMSO-d₆) δ: 2.34 (3H, s), 2.77-2.92 (4H, m), 2.97-3.13 (5H, m),3.32-3.69 (6H, m), 4.04 (1H, m), 4.30 (1H, m), 4.47 (2H, s), 7.16 (1H,s), 7.35 (1H, dd, J=2.1, 8.6), 7.51-7.66 (2H, m), 7.81 (1H, s), 10.57(1H, br), 12.67 (1H, br).

Example 1084-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)-1-piperazinamine

108a) tert-Butyl 4-thioureidopiperazine-1-carboxylate

In the same manner as in Example 66a), the title compound(2.34 g) wasobtained from tert-butyl 4-aminopiperazine-1-carboxylate (WO 0214271:2.0 g) and benzoyl isothiocyanate (1.34 mL).

NMR (CDCl₃) δ: 1.46 (9H, s), 2.56 (2H, m), 2.99 (4H, m), 4.08 (2H, br),6.41 (1H, br), 7.03 (1H, Br), 7.32 (1H, s).

108b) tert-Butyl 4-(1,3-thiazol-2-yl)aminopiperazine-1-carboxylate

In the same manner as in Example 46a), the title compound (1.83 g) wasobtained from the compound (2.3 g) obtained in Example 108a) andchloroacetaldehyde (2.2 mL, a 40% aqueous solution).

NMR (CDCl₃) δ: 1.47 (9H, s), 2.83 (4H, br), 3.55 (4H, br), 6.61 (1H, d,J=3.6), 7.15 (1H, d, J=3.6).

108c)4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-(1,3-thiazol-2-yl)piperazin-1-amine

In the same manner as in Example 46b), the title compound (2.42 g) wasobtained from the compound (1.83 g) obtained in Example 108b) and3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid (1.92 g).

NMR (CDCl₃) δ: 2.80-2.92 (6H, m), 3.53-3.67 (6H, m), 6.18 (1H, br), 6.63(1H, d, J=3.6), 7.16 (1H, d, J=3.6), 7.59 (1H, dd, J=2.1, 9.0),7.88-7.96 (4H, m), 8.47 (1H, s).

108d)4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-N-((2Z)-3-methyl-1,3-thiazol-2(3H)-ylidene)-1-piperazinamine

In the same manner as in Example 57b), the title compound (0.42 g) wasobtained from the compound (0.50 g) obtained in Example 108c) and methyliodide (0.10 mL).

NMR (CDCl₃) δ: 2.68-2.74 (4H, m), 2.86-2.91 (2H, m), 3.28 (3H, s),3.50-3.59 (6H, m), 5.88 (1H, d, J=4.5), 6.41 (1H, d, J=4.5), 7.59 (1H,dd, J=1.5, 7.8), 7.90-7.97 (4H, m), 8.48 (1H, s)

Example 1092-((2Z)-2-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)imino)-1,3-thiazol-3(2H)-yl)ethanol

In the same manner as in Example 57b), the title compound (0.28 g) wasobtained from4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-N-(1,3-thiazol-2-yl)piperazin-1-amine(0.50 g) obtained in Example 108c) and 2-iodoethanol (0.28 mL).

NMR (CDCl₃) δ: 2.70 (4H, m), 2.87 (2H, t, J=8.2), 3.52-3.60 (6H, m),3.88 (4H, s), 5.92 (1H, d, J=4.4), 6.43 (1H, d, J=4.4), 7.59 (1H, dd,J=1.8, 8.8), 7.93-7.97 (4H, m), 8.48 (1H, s).

Example 1102-((2Z)-2-((4-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)imino)-1,3-thiazol-3(2H)-yl)acetamide

In the same manner as in Example 57b), the title compound (0.25 g) wasobtained from4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-N-(1,3-thiazol-2-yl)piperazine-1-amine(0.50 g) obtained in Example 108c) and 2-iodoacetamide (0.30 g).

NMR (CDCl₃) δ: 2.66-2.76 (4H, m), 2.87 (2H, t, J=7.8), 3.53-3.58 (6H,m), 4.30 (2H, s), 5.36 (1H, br), 5.98 (1H, d, J=5.1), 6.52 (1H, d,J=5.1), 6.95 (1H, br), 7.58 (1H, dd, J=2.1, 7.8), 7.89-7.96 (4H, m),8.46 (1H, s).

Example 111(3Z)-7-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-(methylimino)-6,7-dihydro[1,3]thiazolo[3,4-a]pyrazin-8(5H)-one

111a) Ethyl 2-(methylamino)-1,3-thiazol-4-carboxylate

In the same manner as in Example 46a), the title compound (6.42 g) as apale yellow solid was obtained from ethyl bromopyruvate (10 g) andN-methylthiourea.

NMR (CDCl₃) δ: 1.37 (3H, t, J=7.1), 3.01 (3H, d, J=4.9), 4.35 (2H, q,J=7.1), 6.48 (1H, br), 7.40 (1H, s).

111b) tert-Butyl4-((2-hydroxyethyl)((2-(methylamino)-1,3-thiazol-4-yl)carbonyl)amino)piperidine-1-carboxylate

To a solution of the compound (2.00 g) obtained in Example 111a) inethanol (10 mL), a 1 N aqueous sodium hydroxide solution (10 mL) wasadded, and the mixture was mixed for 24 hours. The reaction solution wasneutralized with hydrochloric acid, and the mixture was concentrated.The residue was suspended in acetonitrile (10 mL), and WSC (1.45 g) andHOBt (1.16 g) were added thereto. To the reaction solution, a solutionof tert-butyl 4-((2-hydroxyethyl)amino)piperidine-1-carboxylate (1.24g), N-trimethylsilylacetamide (2.65 g) and triethylamine (1.40 mL) inacetonitrile (10 mL) was added, and the mixture was mixed for 24 hours.The reaction solution was concentrated, and the residue was dissolved inchloroform and a saturated aqueous sodium bicarbonate solution. Theorganic layer was collected by separation, and dried over anhydroussodium sulfate. The solvent was distilled off, and the residue waspurified with a silica gel column to give the title compound (0.66 g) asa pale yellow solid.

NMR (CDCl₃) δ: 1.46 (9H, s), 1.72-1.90 (4H, m), 2.74 (2H, br), 3.99 (3H,d, J=5.2), 3.60 (2H, m), 3.78 (2H, m), 4.18-4.24 (3H, m).

111c) tert-Butyl4-((3Z)-3-(methylimino)-8-oxo-5,6-dihydro[1,3]thiazolo[3,4-a]pyridin-7(8H)-yl)piperidine-1-carboxylate

To a solution of the compound (0.80 g) obtained in Example 111b) and2,6-lutidine (0.54 mL) in dichloromethane (20 mL), trifluoromethanesulfonic acid anhydride (0.38 mL) was added at −40° C. The reactionsolution was heated for 1 hour until the temperature reached roomtemperature, and the reaction solution was poured into chloroform and asaturated aqueous sodium bicarbonate solution. The chloroform layer wascollected by separation, and dried over anhydrous sodium sulfate. Thesolvent was distilled off, and the residue was purified with a silicagel column to give the title compound (0.34 g) as a pale yellow solid.

NMR (CDCl₃) δ: 1.47 (9H, s), 1.55-1.70 (4H, m), 2.76-2.89 (2H, m), 3.01(3H, s), 3.49 (2H, t, J=5.2), 3.84 (2H, t, J=5.2), 4.24 (1H, d, J=12.2),4.71 (1H, m), 6.91 (1H, s). 111d)(3Z)-7-(1-(3-((6-Chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperidinyl)-3-(methylimino)-6,7-dihydro[1,3]thiazolo[3,4-a]pyrazin-8(5H)-one

In the same manner as in Example 46b), the title compound (0.34 g) as acolorless solid was obtained from the compound (0.34 g) obtained inExample 111c) and 3-((6-chloro-2-naphthyl)sulfonyl)propanoic acid.

NMR (CDCl₃) δ: 1.51-1.83 (4H, m), 2.62 (1H, t, J=11.7), 2.80-2.95 (2H,m), 3.00 (3H, s), 3.18 (1H, t, J=11.7), 3.43-3.48 (2H, m), 3.50-3.63(2H, m), 3.81-3.83 (2H, m), 3.96 (1H, d, J=14.1), 4.68 (1H, d, J=14.1),4.80 (1H, m), 6.91 (1H, s), 7.60 (1H, dd, J=1.8, 8.7), 7.88-7.95 (4H,m), 8.47 (1H, s).

Example 112(2S)-3-((6-Chloro-2-naphthyl)sulfonyl)-1-(4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-1-piperazinyl)-1-oxopropan-2-ol

112a) Methyl (2S)-3-[(6-chloronaphthalen-2-yl)thio]-2-hydroxypropionate

Under argon atmosphere, a 3 M solution of ethylmagnesium bromide indiethyl ether was added dropwise to THF (25 mL) with ice cooling. Tothis solution, a solution of 6-chloronaphthalene-2-thiol (5.0 g) in THF(50 mL) was added dropwise at 0C, and the mixture was mixed at roomtemperature for 30 minutes. To this solution, a solution of methyl(2R)-oxirane-2-carboxylate (2.3 mL) in THF (15 mL) was added dropwise,and the reaction solution was mixed at room temperature for 3 hours. Tothe reaction solution, an aqueous ammonium chloride solution (50 mL) wasadded, and the mixture was extracted with ethyl acetate (100 mL). Theextract was washed with saturated brine, dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue wasrecrystallized from hexane/ethyl acetate (3:1) to give the titlecompound (5.9 g, 77%) as colorless needle-shaped crystals.

NMR (CDCl₃) δ: 3.12 (1H, d, J=6.0), 3.35 (1H, dd, J=14.1, 5.7), 3.48(1H, dd, J=14.1, 4.2), 3.58 (3H, s), 4.43-4.48 (1H, m), 7.39-7.43 (1H,m), 7.49-7.52 (1H, m), 7.66-7.69 (2H, m), 7.76-7.77 (1H, m), 7.83-7.84(1H, m).

112b) (2S)-3-[(6-Chloronaphthalen-2-yl)thio]-2-hydroxypropionic acid

To a suspension of methyl(2S)-3-[(6-chloronaphthalen-2-yl)thio]-2-hydroxypropionate (5.4 g)obtained in Example 112a) in ethanol (150 mL), a 8 N aqueous sodiumhydroxide solution (6.8 mL) was added, and the mixture was mixed at roomtemperature for 3 hours. Ethanol was distilled off under reducedpressure, and then the precipitates were collected by filtration. Thesolid was suspended in water (100 mL), pH was adjusted to about 3 with 1N hydrochloric acid, and the precipitates were then collected byfiltration to give the title compound (5.0 g, 97%) as a white solid.

NMR (CD₃OD) δ: 3.27 (1H, dd, J=14.1, 6.9), 3.51 (1H, dd, J=14.1, 4.2),4.33 (1H, dd, J=6.9, 4.2), 7.40-7.43 (1H, m), 7.51-7.54 (1H, m),7.71-7.77 (2H, m), 7.82 (1H, s), 7.86 (1H, s).

112c)(2S)-3-((6-Chloro-2-naphthyl)sulfonyl)-1-(4-(((2Z)-3-methyl-2-(methylimino)-2,3-dihydro-1,3-thiazol-4-yl)methyl)-1-piperazinyl)-1-oxopropan-2-ol

To a suspension of(2S)-3-((6-chloronaphthalen-2-yl)sulfonyl)-2-hydroxypropanoic acid (0.32g),N-((2Z)-3-methyl-4-(-1-piperazinylmethyl)-1,3-thiazol-2(3H)-ylidene)methanaminetrihydrochloride (0.51 g), HOBt (0.20 g) and triethylamine (0.63 mL) inDMF (5 mL), WSC (0.21 g) was added, and the mixture was mixed at roomtemperature for 22 hours. The reaction solution was concentrated underreduced pressure. The residue was basified with an aqueous potassiumcarbonate solution, and then the mixture was extracted with ethylacetate/THF. The extract was dried over anhydrous magnesium sulfate, thesolvent was then distilled off, and the residue was purified with abasic silica gel column to give the title compound (0.12 g, 23%) as acolorless powder.

NMR (CDCl₃) δ: 2.42-2.55 (4H, m), 3.01 (3H, s), 3.28 (2H, s), 3.31-3.43(5H, m), 3.47-3.76 (4H, m), 4.97-5.03 (1H, m), 5.77 (1H, s), 7.59 (1H,dd, J=2.0, 9.0), 7.93-7.97 (4H, m), 8.50 (1H, s)

Preparation Example 1

FXa inhibitors (e.g., therapeutic agent for deep-vein thrombosis,therapeutic agent for cardiogenic cerebral infarction, etc.) comprisingthe compound represented by Formula (1) in the invention or a saltthereof as an active ingredient can be prepared by, for example, thefollowing formulation.

In addition, as ingredients (additives) in addition to the activeingredients in the following formulation, the list of ingredientsaccording to Japanese Pharmacopoeia, Japanese Standards forPharmaceutical Ingredients or Standards for Pharmaceutical additives canbe used. 1. Capsule (1) Compound obtained in Example 12 120 mg (2)Lactose 210 mg (3) Microcrystalline cellulose  27 mg (4) Magnesiumstearate  3 mg 1 Capsule 360 mg(1), (2), (3) and ½ of (4) were mixed and then granulated. The remaining(4) was added thereto, and the whole mixture was encapsulated in agelatin capsule.

2. Capsule (1) Compound obtained in Example 83 120 mg (2) Lactose 210 mg(3) Microcrystalline cellulose  27 mg (4) Magnesium stearate  3 mg 1Capsule 360 mg(1), (2), (3) and ½ of (4) were mixed and then granulated. The remaining(4) was added thereto, and the whole mixture was encapsulated in agelatin capsule.

3. Tablet (1) Compound obtained in Example 12 120 mg (2) Lactose 174 mg(3) Corn starch  54 mg (4) Microcrystalline cellulose 10.5 mg  (5)Magnesium stearate  1.5 mg 1 Tablet 360 mg(1), (2), (3), ⅔ of (4) and ½ of (5) were mixed and then granulated. Theremaining (4) and (5) were added to the granules, and the mixture wascompressed to give tablets.

4. Tablet (1) Compound obtained in Example 83 120 mg (2) Lactose 174 mg(3) Corn starch  54 mg (4) Microcrystalline cellulose 10.5 mg  (5)Magnesium stearate  1.5 mg 1 Tablet 360 mg(1), (2), (3), ⅔ of (4) and ½ of (5) were mixed and then granulated. Theremaining (4) and (5) were added to the granules, and the mixture wascompressed to give tablets.

Preparation Example 2

50 mg of the compound obtained in Example 12 was dissolved in 50 mL ofthe distilled water for injection according to Japanese Pharmacopoeia,and then the distilled water for injection according to JapanesePharmacopoeia was added to a volume of 100 mL. The solution was filteredunder the sterilized condition, and then taken out in 1 mL-portions, andunder sterilized condition, charged into a vial for injection. The vialswere freeze-dried for sealing.

Experimental Example

(1) Inhibitory Action of Human Activated Blood Coagulation Factor X(FXa):

Test method: A solution (225 μL) of 0.05M tris-hydrochloric acid buffers(pH=8.3) containing 0.145 M of sodium chloride and 2 mM of calciumchloride, a test compound dissolved in dimethyl sulfoxide (5 μL) andhuman FXa (10 μL, 0.3 unit/ml) were added to a 96-well microplate andreacted at 37° C. for about 10 minutes, and then a substrate (10 μL, 3mM, S-2765) was added to be reacted at 37° C. for 10 minutes. Then,after aqueous 50% acetic acid (25 μL) was added there to stop thereaction, the change of absorbance at 405 nm was measured by amicroplatereader, and a concentration inhibiting FXa activity by 50%(IC₅₀) was calculated.

(2) Measurement of in vitro Coagulation Time

(2-1) Measurement of Extrinsic Coagulation Time (PT):

The extrinsic coagulation time was measured with an automatic bloodcoagulation time measuring apparatus (STA compact, DIAGNOSTICA STAGO)using a PT reagent (DIAGNOSTICA STAGO). 3 μl of the drug was added to 97μl of human normal plasma (fresh human plasma (FFP), SEKISUI CHEMICALCo., Ltd.) and preliminarily warmed to 37° C. for 4 minutes. To 50 μl ofthe aforementioned plasma, 100 μl of a rabbit-brain-derived tissuethromboplastin solution was added, and then the time taken tocoagulation was measured. The drug was used after dissolving in dimethylsulfoxide (DMSO). The concentration for doubling the coagulation timewas calculated based on the coagulation time obtained when DMSO wasadded instead of the drug.

(2-2) Measurement of Intrinsic Coagulation Time (APTT):

The intrinsic coagulation time was measured with an automatic bloodcoagulation time measuring apparatus using an STA-APTT-LT (DIAGNOSTICASTAGO). 3 μl of the drug was added to 97 μl of human normal plasma. To50 μl of the plasma, 50 μl of an active partial thromboplastin solutionwas added, and preliminarily warmed to 37° C. for 4 minutes. 50 μl of a25 mmol/l CaCl₂ solution was added, and the time taken to coagulationwas measured. The drug was used after dissolving in DMSO. Theconcentration for doubling the coagulation time was calculated in thesame manner as in (2-1).

(2-3) Measurement of Thrombin Coagulation Time (TT).

The thrombin coagulation time was measured with an automatic bloodcoagulation time measuring apparatus using a fibrinogen reagent(DIAGNOSTICA STAGO). The fibrinogen reagent (containing thrombin) wasdissolved in 5 mL of distilled water, and then was conditioned bydiluting to 20-folds with 0.5% bovine serum albumin-added physiologicalsaline. 3 μl of the drug was added to 97 μl of human normal plasma(fresh human plasma (FFP), SEKISUI CHEMICAL Co., Ltd.), and waspreliminarily warmed to 37° C. for 3 minutes. To 50 μl of theabove-described plasma, 100 μl of the thrombin solution was added, andthe time taken to coagulation was measured. The drug was used afterdissolving in DMSO. The concentration for doubling the coagulation timewas calculated in the same manner as in (2-1).

(3) Measurement of ex vivo Coagulation Time (Mouse)

(3-1) Intravenous Administration:

Male ICR mice (25 to 35 g, CREA Japan, Inc.) were used. Underpentobarbital (50 mg/kg, i.p.) anesthesia, the drug was administeredonce in a dose of 5 mL/kg from the tail vein of each mouse. After 5minutes of administration, 0.8 mL of blood was collected from theabdominal aorta or heart using 1/10 of 3.8% sodium citrate (Citral,YAMANOUCHI PHARMACEUTICAL Co., Ltd.), and was centrifuged at 3000 rpmfor 15 minutes to obtain the plasma. To 50 μl of the plasma, 100 μl of arabbit brain-derived tissue thromboplastin solution was added, and thenthe time taken to coagulation was measured. The coagulation time wasmeasured with an automatic blood coagulation time measuring apparatus(STA compact) using a PT reagent (DIAGNOSTICA STAGO). The drug was usedafter dissolving in a mixed solution containing dimethylacetamide, 1/10N hydrochloric acid and physiological saline solution, and for thecontrol, a mixed solution containing dimethylacetamide, 1/10 Nhydrochloric acid and physiological saline solution was administeredinstead of the drug. The drug activity was indicated as a ratio (%) ofthe coagulation time for the drug administered group to the coagulationtime for the control.

(3-2) Oral Administration:

Male ICR mice (25 to 35 g, CREA Japan, Inc.) were used. Each mouse whichhad fasted for over 12 hours was forcibly subjected to oraladministration of the drug in a dose of 5 mL/kg. After 1 hour ofadministration, blood was collected from the abdominal aorta underpentobarbital (50 mg/kg, i.p.) anesthesia. The drug was used aftersuspending in a 0.5% methylcellulose solution, and for the control, a0.5% methylcellulose solution was administered instead of the drug. Theother conditions were provided in the same manner as in (3-1).

(4) Measurement of in vivo Antithrombotic Effect

(4-1) Rat Arteriovenous Shunt Method:

The rat arteriovenous shunt method was carried out according to themethod of Umetsu, et al., Thromb. Haemostas., 39, 74-73 (1978) Male SDrats (200 to 350 g, CREA Japan, Inc.) were used, and under pentobarbital(50 mg/kg, i.p.) anesthesia, an extracorporeal circuit was establishedusing a polyethylene tube having a silk thread attached, between theleft jugular vein and the right jugular vein of each rat. In order toprevent blood coagulation, the tube was filled in advance withphysiological saline containing heparin (50 U/mL). The blood wascirculated for 15 minutes, and the wet weight of thrombi adhered to thesilk thread during the circulation was measured. The drug wasadministered via oral or intravenous administration. In the case of oraladministration, the drug was administered (2 mL/kg) after suspending ina 0.5% methylcellulose solution, with the rat having fasted, and for thecontrol, a 0.5% methylcellulose solution was administered instead of thedrug. In the case of intravenous administration, the drug was dissolvedin physiological saline and was administered in a dose of 1 mL/kg fromthe tail vein, and for the control, physiological saline wasadministered instead of the drug. The drug activity was calculated as aratio (%) of the wet weight of thrombi in the drug administered group tothe wet weight of thrombi in the control group.

(4-2) Model of Rat Abdominal Vena Cava Partial Ligation

Male SD rats (200 to 400 g, CREA Japan, Inc.) were used. Underpentobarbital (50 mg/kg, i.p.) anesthesia, the abdominal vena cava ofeach rat was carefully removed, and then threads were placed at therenal vein bifurcation of the abdominal vena cava and at a position 1 cmdistal to the bifurcation, thus to ligate all of the rami present inbetween. A balloon catheter (Fogarty 2F, BAXTER HEALTHCARE Corp.) wasintroduced from the left femoral vein, and the area in between the twothreads was injured three times using the balloon expanded with 200 to300 mL of air. The balloon catheter was removed, the thread placed atthe renal vein bifurcation was tied together with a 26 G needle, andthen the needle was removed to provide a partial ligation. After 30minutes, another thread was tied, the thrombi obtained from between thetwo threads were carefully isolated, and the wet weight of thrombi wasmeasured with an analytical balance equipped with windshield (BP110S,SATORIUS AG). The drug was administered via oral or intravenousadministration, in the same manner as in (4-1). The drug activity wascalculated in the same manner as in (4-1).

(4-3) Model of Rat Deep Vein Thrombosis (DVT)

Male SD rats (200 to 350 g, CREA Japan, Inc.) were used. Underpentobarbital (50 mg/kg, i.p.) anesthesia, a polyethylene tube wasinserted into the left femoral vein of each rat. A silk thread (length 5cm) preliminarily connected to a guide wire was inserted into thepolyethylene tube, and the tube was filled with physiological salinecontaining heparin (50 U/mL) in order to prevent blood coagulation.After inserting the polyethylene tube until the tube reached theabdominal vena cava, the silk thread was fixed in the abdominal venacava using the guide wire. After 30 minutes of the fixing, heparin (200U/kg) was intravenously administered from the tail vein. The rat wasexsanguinated by cutting the brachial artery, and then was subjected toabdominal celiotomy to take out the silk thread, and the wet weight ofadhered thrombi (including the weight of the silk thread) was measured.The drug was administered via oral or intravenous administration, in thesame manner as in (4-1). The wet weight of thrombi only was determinedfrom the calculation formula: (wet weight of thrombi adhered to the silkthread)−(wet weight measured by immersing a silk thread in theheparin-collected venous blood). The drug activity was calculated in thesame manner as in (4-1).

Experimental Results

The IC₅₀ values determined in Experimental Example (1) are presented inTable 1. It is obvious from the results that the compound of theinvention has an excellent FXa inhibiting effect. TABLE 1 Example No.IC₅₀ (nM) Example No. IC₅₀ (nM)  5 57 12 22 38 11 44 14 46 30 58 60 688.3 77 9.4 83 6.7 92 47

INDUSTRIAL APPLICABILITY

Compound (I) of the present invention has excellent FXa inhibitingeffect, and is useful as an anti-coagulant capable of oral uptake andhaving less side effect of hemorrhage. Compound (I) of the invention isadvantageously used for the prevention and/or treatment of variousdiseases caused by thrombus and infarction.

1. A compound represented by Formula (I):

wherein R is a cyclic hydrocarbon group which may be substituted or aheterocyclic group which may be substituted; X is a bond or a divalentchain hydrocarbon group which may be substituted; X′ is a bond or—N(R⁵)— (wherein R⁵ is a hydrogen atom, a hydrocarbon group which may besubstituted, an esterified or amidated carboxyl group, or an acylgroup); Y is a divalent hydrocarbon group which may be substituted; Y′is a bond or —C(═O)—; ring A is a nitrogen-containing heterocycle whichmay be substituted; Z¹ and Z³ are each independently a bond or adivalent chain hydrocarbon group which may be substituted; Z² is a bondor —N(R⁶)— (wherein R⁶ is a hydrogen atom, a hydrocarbon group which maybe substituted, or an acyl group); B is a group represented by theformula:

(wherein R¹ and R² are each independently a hydrogen atom, a halogenatom, a hydrocarbon group which may be substituted, an alkoxy groupwhich may be substituted, a carboxyl group which may be esterified oramidated, an acyl group, or an amino group which may be substituted; R³is a hydrogen atom, a hydrocarbon group which may be substituted, acarboxyl group which may be esterified or amidated, or an acyl group; R⁴is a hydrocarbon group which may be substituted; and R² and R¹ or R⁴,and R³ and R⁴ may be respectively bonded to each other to form a ringwhich may be substituted); R⁶ and R¹, R², R³ or R⁴ may be bonded to eachother to form a ring which may be substituted; and a is 0, 1 or 2, or asalt thereof.
 2. A prodrug of the compound according to claim
 1. 3. Thecompound according to claim 1, wherein R is an aryl group which may besubstituted with a substituent selected from a halogen atom, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, amino which may be substituted, nitro,cyano, amidino which may be substituted, and carboxyl which may beesterified or amidated.
 4. The compound according to claim 1, wherein Ris a heterocyclic group which may be substituted with a substituentselected from a halogen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,amino which may be substituted, nitro, cyano, amidino which may besubstituted, and carboxyl which may be esterified or amidated.
 5. Thecompound according to claim 1, wherein R is naphthyl which may besubstituted with a halogen atom.
 6. The compound according to claim 1,wherein X is a bond, X′ is a bond, Y is C₁₋₃ alkylene which may besubstituted, and Y′ is —C(═O)—.
 7. The compound according to claim 6,wherein Y is C₁₋₃ alkylene substituted with a hydroxyl group.
 8. Thecompound according to claim 1, wherein Z¹ and Z are each a bond, and Z³is C₁₋₃ alkylene which may be substituted.
 9. The compound according toclaim 1, wherein ring A is a piperazine ring which may be substituted ora piperidine ring which may be substituted.
 10. The compound accordingto claim 1, wherein ring A is a ring represented by the formula:

wherein ring A′ may be further substituted, or the formula:

wherein ring A″ may be further substituted.
 11. The compound accordingto claim 1, wherein R⁵ is a hydrogen atom.
 12. The compound according toclaim 1, wherein a is
 2. 13. A compound selected from the groupconsisting ofN-(4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine,4-((4-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-1-piperazinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-imine,N-(5-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)methyl)-3-methyl-1,3-thiazol-2(3H)-ylidene)-N-methylamine,5-(1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)-3-methyl-1,3-thiazol-2(3H)-imine,and2-(2-((1-(3-((6-chloro-2-naphthyl)sulfonyl)propanoyl)-4-piperidinyl)imino)-1,3-thiazol-3(2H)-yl)ethanol,or a salt thereof or a prodrug thereof.
 14. A compound represented byFormula (II′)

wherein P⁰ is a hydrogen atom, or a protective group for imino group;and the other symbols have the same meanings as defined in claim 1, or asalt thereof.
 15. A pharmaceutical composition comprising the compoundaccording to claim 1 or
 2. 16. The pharmaceutical composition accordingto claim 15, which is an anticoagulant.
 17. The pharmaceuticalcomposition according to claim 15, which is an activated bloodcoagulation factor X inhibitor.
 18. The pharmaceutical compositionaccording to claim 15, which is a medicament for preventing or treatingmyocardial infarction, cerebral infarction, deep vein thrombosis,pulmonary thromboembolism or atherosclerotic obliterans.
 19. Thepharmaceutical composition according to claim 15, which is a medicamentfor preventing or treating economy-class syndrome, thromboembolismduring and post operation, or the secondary onset of deep veinthrombosis.
 20. A method for inhibiting blood coagulation in a mammal,which comprises administering an effective amount of the compoundaccording to claim 1 or a prodrug thereof to a mammal.
 21. The methodfor inhibiting an activated blood coagulation factor X in a mammal,which comprises administering an effective amount of the compoundaccording to claim 1 or a prodrug thereof to a mammal.
 22. The methodfor preventing or treating myocardial infarction, cerebral infarction,deep vein thrombosis, pulmonary thromboembolism or atheroscleroticobliterans in a mammal, which comprises administering an effectiveamount of the compound according to claim 1 or a prodrug thereof to amammal.
 23. Use of the compound according to claim 1 or a prodrugthereof, for manufacturing a medicament for inhibiting bloodcoagulation.
 24. Use of the compound according to claim 1 or a prodrugthereof, for manufacturing a medicament for inhibiting an activatedblood coagulation factor X.
 25. Use of the compound according to claim 1or a prodrug thereof, for manufacturing a medicament for preventing ortreating myocardial infarction, cerebral infarction, deep veinthrombosis, pulmonary thromboembolism or atherosclerotic obliterans.